Anesthesiology: Volume 93(3) September 2000 pp 858-875

Local Anesthetics and the Inflammatory Response: A New Therapeutic Indication?

Hollmann, Markus W. M.D*; Durieux, Marcel E. M.D., Ph.D. Section Editor(s) !isher, Dennis M. Editor *"esearch !ello#. $ssociate Pro%essor o% $nesthesiolo&' and (eurolo&ical Sur&er' and $ssistant Pro%essor o% Pharmacolo&'. )ndi*idual article re+rints ma' ,e +urchased throu&h the -ournal We, site, ###.anesthesiolo&'.or& "ecei*ed %rom the De+artment o% $nesthesiolo&', .ni*ersit' o% /ir&inia, 0harlottes*ille, /ir&inia. Su,mitted %or +u,lication $u&ust 12, 3444. $cce+ted %or +u,lication $+ril 15, 1666. Su++orted in +art ,' an $merican Heart $ssociation &rant (/H$ 4416789.), Mid:$tlantic $%%iliation, ;altimore, Mar'land, to Dr. Hollman and /$ and (ational )nstitutes o% Health &rant <MS 917=2, ;ethesda, Mar'land. $ddress re+rint re>uests to Marcel E. Durieux, M.D., Ph.D., De+artment o% $nesthesiolo&', .ni*ersit' o% /ir&inia Health Sciences 0enter, P.?. ;ox 36636, 0harlottes*ille, /ir&inia 11465:6636. $ddress electronic mail to: durieux@virginia.edu LOCAL anesthetics (LA) are known for their ability to block a@ channels. !owever" they have significant effects in several settings other than local and regional anesthesia or antiarrhyth#ic treat#ent" the areas in which they are used traditionally. $hese effects result fro# LAs interacting with other cellular syste#s as well. %nterestingly" so#e of these effects occur at concentrations #uch lower than those re&uired for a@ channel blockade. 'or exa#(le" whereas the half)#axi#al inhibitory concentration (%C*+) of lidocaine at the neuronal a@ channel is a((roxi#ately *+),++ -# (de(ending on the s(ecific channel subty(e and study (re(aration)" 1 the co#(ound inhibits signaling through #, #uscarinic rece(tors (ex(ressed reco#binantly in Xenopus laevis oocytes) with an %C*+ of .+ n#" that is" ,"+++) to *"+++)fold lower. 2 $his sensitivity of other targets has two i#(ortant conse&uences. 'irst" we assu#e that LAs" at concentrations that result in significant a@ channel blockade" also affect a nu#ber of other syste#s. /econd" relatively low LA concentrations (such as attained in blood during e(idural anesthesia or analgesia or during intravenous LA infusion) that block neuronal a@ channels to a li#ited extent only still can have significant (har#acologic effects. 0e suggest that so#e of these alternative actions #ay be beneficial in the clinical setting" and others #ay be res(onsible for so#e adverse effects of LAs. Although 1utterworth and /trichart2 3 a decade ago urged investigation of such actions and their #echanis#s" #uch re#ains to be discovered. $o de#onstrate the variety of LA effects" table 1 (rovides an overview of various LA actions re(orted in the literature.

$his review focuses on an area in which alternative actions of LAs show #uch (ro#ise for clinical a((lication: their effects on the infla##atory res(onse and es(ecially on infla##atory cells (#ainly (oly#or(honuclear granulocytes 345 s6 but also #acro(hages and #onocytes). 45 s do not ex(ress a channels" and LA effects on these cells therefore are not caused by a channel blockade. LA effects on these cells are not affected by a channel blockers such as tetrodotoxin or veratridine. 5 Overactive infla##atory res(onses that destroy rather than (rotect are critical in the develo(#ent of a nu#ber of (erio(erative disease states" such as (osto(erative (ain" !-8 adult res(iratory distress syndro#e (A78/)" 9-11 syste#ic infla##atory res(onse syndro#e" and #ultiorgan failure. 12-15 4erio(erative #odulation of such res(onses is therefore relevant to the (ractice of anesthesiology" and LAs #ay (lay significant roles in this regard. Inflammatory Response %n general ter#s" infla##ation can be described as a reaction of the host against in9urious events such as tissue trau#a or (resence of (athogens. 7elease of vasoactive #ediators fro# tissue #ast cells (hista#ine" leukotrienes)" as well as fro# (latelets and (las#a co#(onents (bradykinin)" causes vasodilation and

increased vascular (er#eability" leading to the classic infla##atory signs of redness (rubor) and heat (calor). $he resulting ede#a causes swelling (tumor)" and interactions of infla##atory #ediators with the sensory syste#s induce (ain (dolor). /ignificant local infla##ation causes a syste#ic res(onse" ter#ed the acute phase reaction. $his res(onse is #anifested by increases in acute (hase (roteins (C)reactive (rotein" co#(le#ent factor C:" fibrinogen" and seru# albu#in)" followed by activation of several syste#s of #ediators (kinin syste#" co#(le#ent syste#" li(id #ediators" and cytokines). Cytokines" in (articular" are i#(ortant for regulation of the infla##atory res(onse. $he local release of cytokines (interleukin), 3%L),6" %L);" tu#or necrosis factor 3$ '6) coordinates the infla##atory res(onse at the site of in9ury and induces neutro(hil che#otaxis to the site of infla##ation. /o#e cytokines (%L)," %L)<" $ ') released fro# infla##atory sites #ediate the syste#ic res(onse. $hey induce fever and the acute (hase reaction" #obili2e neutro(hils fro# the bone #arrow" and (ro#ote ly#(hocyte (roliferation. $he infla##atory res(onse induces cells ((ri#arily 45 s and #onocytes) to #igrate into the affected area" in which they destroy (athogens" largely by (hagocytosis. $his (rocess can be divided into several stages ("ig# 1):

'ig. ,. /tages of the infla##atory res(onse: (,) sensing of che#oattractants by (oly#or(honuclear granulocytes= (.) #argination and adhesion= (:) dia(edesis= (>) che#otaxis= (*) o(soni2ation= (<) generation of reactive oxygen #etabolites= (?) (hagocytosis. A84! @ nicotina#ide adenine dinucleotide (hos(hate.

45 s sense che#oattractants derived fro# bacteria" co#(le#ent activation" and cytokine (roduction at the site of infection. 45 s roll onto and attach to endothelial cells (#argination and adhesion). Adhesion is #ediated by hista#ine" co#(le#ent factors C*a and C:a" %L), and %L);" and $ ' and (latelet)activating factor. 45 s s&uee2e through ga(s between ad9acent endothelial cells (dia(edesis). 45 s #igrateu( the che#oattractant gradient to the (athogen (che#otaxis). C*a" C:a" %L);" and leukotriene 1> (L$1>) and other cytokines are involved in che#otaxis. 4athogens are o(soni2ed (coated with s(ecific seru# (roteins" such as co#(le#ent frag#ents" i##unoglobulins" or acute (hase (roteins) and 45 s are (ri#ed (switched to an activated state with increased surface ex(ression of (las#a #e#brane rece(tors and enhanced nicotina#ide adenine dinucleotide (hos(hate 3 A84!6)oxidase activity). 45 s generate reactive oxygen #etabolites (O. :" !.O." O!" and (articularly !OCl) using A84!) oxidase or #yelo(eroxidase en2y#e co#(lexes. %ncreased oxygen u(take (inde(endent fro# #itochondrial res(iration) is re&uired for generation of free radicals and is referred to as respiratory burst. 45 s deliver free radicals to the (athogen. 4athogens are killed by (hagocytosis (by 45 s and #ononuclear (hagocytes) and)in 45 s)by delivery of high concentrations of reactive oxygen #etabolites into the (hagoso#e. $his infla##atory res(onse can be enhanced further by 45 (roducts. $he infla##atory res(onse is essential for structural and functional re(air of in9ured tissue. %t is" however" a double)edged sword. Axcessive generation of (roinfla##atory signals" as occurs in several disease states" can aggravate tissue da#age because of (roducts derived fro# infla##atory cells. $his suggests that #odulation of the infla##atory res(onse (e.g." by LAs) #ight (revent such tissue da#age. Effects of LAs on Inflammatory Processes $his section describes so#e actions of LAs on infla##atory (rocesses. 0e focus on three s(ecific disease states relevant to anesthesiologists: infla##atory lung in9ury" increased #icrovascular (er#eability" and #yocardial ische#ia)re(erfusion in9ury. %n addition" we discuss briefly the use of LAs to treat infla##atory bowel disease" an area of active clinical investigation. 'inally" we refer to an issue of considerable i#(ortance: the (ossibility that LAs" because of their antiinfla##atory (ro(erties" #ight increase the risk of infection in certain settings. !igh LA concentrations have been used in so#e studies" and" in order to 9udge the clinical relevance of the various re(orts" it is i#(ortant to consider the concentrations of LAs used in clinical (ractice. $hese concentrations differ widely" de(ending on the #ethod of a((lication. %n order to achieve syste#ic effects after intravenous ad#inistration of LAs" (las#a levels in the low #icro#olar range are re&uired (for lidocaine" a((roxi#ately +.*)*.+ -gB#l" corres(onding to .).+ -#)=1! 'or exa#(le" intravenous ad#inistration of lidocaine at .)> #gB#in leads to (las#a concentrations of ,): -gB#l (>),. -#) after ,*+ #in. 17 After ,* #in a . #gBkg intravenous bolus of lidocaine results in (eak (las#a levels of ,.*),.C -gB#l (<); -#). 18 /i#ilar (las#a concentrations are obtained after e(idural ad#inistration 19 or to(ical a((lication of LAs (, #gBc#1) in (artial)thickness burns 20= LAs a((lied to(ically on intact skin are likely to achieve substantially lower (las#a concentrations. 4las#a concentrations of lidocaine above ,+ -gB#l tend to (roduce adverse effects. 21 %n contrast" after local a((lication or tissue infiltration of these drugs" LA tissue concentrations are ty(ically in the #illi#olar range. /i#ilar concentrations are (resent around the s(inal nerves after e(idural or s(inal ad#inistration of LAs. 22 LA concentrations at s(ecific sites vary widely" de(ending on the #ethod of ad#inistration. In vivo" LAs are largely (rotein)bound" lowering the concentrations available for interactions with signaling syste#s. 5ost studies have used lidocaine as a (rototy(ical co#(ound. Although other LAs a((ear to exhibit largely si#ilar actions" there is clearly a lack of co#(arative studies with LAs fro# various classes" and very few structure)function studies have been (erfor#ed. 8ata obtained with lidocaine cannot necessarily be extra(olated to other LAs.

Effects of LAs on Lung Injury 4oly#or(honuclear granulocytes" #acro(hages" and cytokines (lay crucial roles in the (athogenesis of infla##atory lung in9ury. Cytokines increase the ex(ression of adhesion #olecules" thereby increasing #argination of 45 accu#ulated in the lung. $he attach#ent of 45 affects endothelial cells and #icrovascular (er#eability. ishina et al. 23 re(orted that (re) or early (osttreat#ent with lidocaine (bolus . #gBkg D . #g E kg:3 E h: 3 continuous infusion" yielding (las#a concentrations of ,..)..* -gB#l 3*),+ -#6) attenuates the late (hase of acid installation)induced lung in9ury in rabbits. Lidocaine decreased 45 accu#ulation in the lung. /u(eroxide anion (roduction by 45 s obtained fro# the (ul#onary artery was inhibited" indicating reduced free radical generation. %n turn" this would reduce endothelial da#age and therefore #ight decrease (ul#onary ede#a. $he !Cl)induced increase in (ul#onary wet:dry ratio and albu#in extravasation was attenuated in lidocaine)treated rabbits" and cytokine levels in bronchoalveolar fluid decreased. ('luid used for bronchoalveolar lavage routinely contains high concentrations of LA in clinical 2 and ani#al ex(eri#ents. 25 $hese concentrations of LA have been shown to affect the behavior of alveolar #acro(hages significantly. 2!) $he decrease in cytokines was #ore likely a result fro# attenuation of the infla##atory res(onse" rather than direct su((ression of cytokine (roduction by #acro(hages or alveolar e(i) and endotheliu#. 4las#a levels of %L)< and %L);" and %L)< concentrations in bronchoalveolar fluid" were less in lidocaine)treated ani#als. $he antiinfla##atory effects of lidocaine i#(roved lung function after tracheal !Cl installation" indicated by i#(roved (artial (ressure of oxygen and attenuation of both decreased co#(liance and increased resistance. $he (rotective effects observed were likely a result of inhibition of se&uestration and activation of 45 s. 23 %nteractions of 45 s with endothelial cells also #ay be i#(ortant in the (athogenesis of organ dysfunction induced by endotoxin. %ncreased #argination of activated 45 in res(onse to an infla##atory sti#ulus contributes to endothelial da#age. 1ecause LAs interfere with the initial ste(s of infla##ation in vitro" a (rotective effect of these drugs in endotoxin)induced lung in9ury #ight be ex(ected. /ch#idt et al. 27 re(orted that" in a rat #odel of se(sis" (retreat#ent with lidocaine ((las#a concentration ,.>)..* -gB#l 3<),+ -#6) attenuated endotoxin)induced increases in 45 adherence" 45 activation and #igration to the infla##atory site" and 45 #etabolic function" as assessed by an inhibition of free radical (roduction. $he (rotective action of lidocaine was not a result of differences in venular wall shear rate. %nstead" inhibition of 45 adherence to endothelial cells" 45 function" and su((ression of hista#ine release by lidocaine #ay ex(lain the observed decrease of #icrovascular (er#eability in lidocaine)(retreated rats. /i#ilar results were obtained by 5ikawa et al., 28 who showed that (retreat#ent with lidocaine (single dose of . #gBkg intravenously followed by continuous infusion of . #g E kg:3 E h:3) significantly attenuates endotoxin)induced lung in9ury in rabbits" by attenuating the accu#ulation and the O. : (roduction of 45 s. $he #echanis#s underlying A78/ induced by long)ter# ex(osure to high oxygen concentrations re#ain unclear. An infla##atory #echanis#" including 45 activation and se&uestration in the lung" #ay be (ivotal in the (athogenesis of this syndro#e. $his hy(othesis is confir#ed by the fact that antioxidants (rotect the lung in such situations. Considering the effects of LAs on infla##atory cells" it would be ex(ected that their antiinfla##atory (ro(erties hel( (revent hy(eroxic lung in9ury. $akao et al. 29 de#onstrated a (rotective effect of LAs on infla##atory res(onses and (ul#onary function in a rabbit #odel of hy(eroxia)induced lung in9ury. Lidocaine infusion to syste#ically relevant (las#a concentrations (,.>)..* -gB#l 3<),+ -#6) decreased che#otactic factors (C:a" C*a" $ ')F" %L),G) in bronchoalveolar lavage fluid and resulted in less 45 accu#ulation than in saline)infused rabbits. 45 fro# lidocaine) treated rabbits showed a #arked reduction in che#ilu#inescence" indicating reduced free radical release and therefore less likelihood of endothelial da#age. $he treated ani#als develo(ed less lung ede#a" as de#onstrated by a decrease in albu#in extravasation and i#(roved wet:dry ratio of the lung. Lidocaine infusion was associated with fewer histo(athologic changes of lung da#age. LAs have been shown to be (rotective in various ani#al #odels of A78/" and the underlying #echanis# a((ears to be their antiinfla##atory action.

Effects of LAs on icro!ascular Permea"ility %ncreased #icrovascular (er#eability is co##on in #any infla##atory diseases. Axa#(les relevant to anesthesiologists include A78/" se(sis" burns" and (eritonitis. Harious studies have shown (rotective effects of LAs on this (rocess. %n an in vivo #odel of ligature)induced obstructive ileus in rats" lidocaine" ad#inistered intravenously (. #gBkg) or s(rayed directly onto the serosa" su((ressed the infla##atory reaction" as indicated by #arked inhibition of fluid secretion and albu#in extravasation. 30 Although blockade of neurons in the enteric nervous syste# (es(ecially the #yenteric (lexus)" with subse&uent reduction in the release of secretory #ediators such as vasoactive intestinal (oly(e(tide" #ay have contributed to the antisecretory action of lidocaine" this does not ex(lain easily why lidocaine (retreat#ent of the serosa of the obstructed 9e9unu# reduced the infla##atory reaction in the bowel wall even ,; h later. LidocaineIs interference with several ste(s of the infla##ation cascade #ay be a #ore likely ex(lanation for the (rotective effect observed in this study. 31 /i#ilar results were obtained by 7i#bJck et al. 30 $hey studied the effects on !Cl)induced (eritonitis of to(ical (re) and (osttreat#ent of the (eritoneal surface with lidocaine (:? ##) and bu(ivacaine (,?.* ##). 1oth anesthetics significantly inhibited Avans blue albu#in extravasation" a #arker of #icrovascular (er#eability. Although both drugs were titrated to the sa#e nonioni2ed fraction (based on (Ka)" lidocaine showed a #ore (otent inhibitory effect. 30 Lsing ha#ster cheek (ouch" 5artinsson et al. 32 observed reversible inhibition by ro(ivacaine (,++ -#) of L$1>)induced (las#a exudation" indicating that the effect is not s(ecific to lidocaine. $her#al in9ury activates the co#(le#ent syste# and other infla##atory cascades" resulting in (rogressive (las#a extravasation with subse&uent hy(o(roteine#ia and hy(ovole#ia. Antiinfla##atory drugs inhibit burn)induced albu#in extravasation" 33$3 suggesting a role for infla##atory #ediators in the (athogenesis of ede#a. $herefore investigators were interested in studying whether the anti)infla##atory (ro(erties of LAs could (rotect #icrovascular integrity" without increasing infection rate. Lsing skin burns in rats" Cassuto et al. 35 re(orted that to(ical a((lication or syste#ic ad#inistration of a#ide LAs" in doses resulting in (las#a concentrations below toxic level" 17$20 significantly inhibited (las#a exudation in rats co#(ared with (lacebo. $his (rotective action could be ex(lained by several of the known effects of LAs. %nhibition of 45 delivery to the site of infla##ation" 3! direct su((ression of 45 )endothelial adhesiveness" 37 reduced generation of toxic oxygen #etabolites" 38$39 i#(aired (rostaglandin and leukotriene (roduction 33$ 0 or increased local (rostacyclin (roduction" 1 and reduced 45 stickiness and adherence to in9ured endotheliu# all #ay contribute to the reduced (las#a extravasation. $hese findings were not confir#ed" however" by ishina et al." 23 who did not find that LAs affect leukotrienes and (rostacyclin. %nhibition of sensory neurons with resultant decreases in release of substance 4" suggested to be i#(ortant for ede#a develo(#ent after ther#al in9ury" 2 is another (ossible ex(lanation. Cassuto et al. 35 re(orted that the (rotective effect was lost if the syste#ically ad#inistered concentration of lidocaine was increased fro# ,+ to :+ -g E kg:3 E #in:3. A (otential ex(lanation for this unusual concentration)de(endency is activation or block of additional (athways at the higher lidocaine concentration. A si#ilar and (ossibly related (heno#enon is the concentration)de(endent action of LAs on vascular s#ooth #uscle in vitro and in vivo : 3 Low concentrations (for lidocaine , -gB#l), #gB#l" corres(onding to > -#)> ##) induce vasoconstriction= greater concentrations induce vasodilation. %t is conceivable that vasoconstriction would decrease ede#a for#ation" and vasodilation would enhance it. %nhibiting the infla##atory res(onse could increase the incidence of infection" but 1rofeldt et al. 20 re(orted that *M lidocaine crea#" a((lied to the skin of (atients with (artial)thickness burns in concentrations u( to ...* #gBc#1" was associated with good (ain relief" (las#a concentrations below toxic levels" no infections or allergic co#(lications" and excellent wound healing. $hese studies suggest that benefit #ay be obtained fro# to(ical treat#ent with LAs" even in (atients with extensive burns. Effects of LAs on Inflammatory #iseases of the $astrointestinal Tract %nfla##atory (rocesses contribute to the develo(#ent of several bowel diseases. Llcerative colitis and (roctitis are caused by both i##unologic and infla##atory sti#uli. %n a rat colitis #odel" ro(ivacaine showed (rotective effects" 32$ and clinical studies have shown that LAs can be effective against the

severe #ucosal infla##ation of these diseases. 5$ ! Arlander et al. 7 re(orted that (atients with ulcerative colitis treated rectally with ro(ivacaine .++ #g twice daily (#ean (eak (las#a concentrations ,.+),.> -gB#l 3:.<)*.+ -#6) de#onstrated decreased infla##ation and reduced clinical sy#(to#s after only . weeks of treat#ent. 4erturbation of the link between infla##atory and i##unoco#(etent cells" as well as blockade of hy(erreactive autono#ic nerves (which also #ay (lay a causative role in these diseases)" 8 were suggested as (ossible ex(lanations for the LA effect. 8ecreased release of (roinfla##atory li(oxygenase (roducts (L$1> or *)hydroxy)eicosatetraenoic acid)" with other (otentially cyto(rotective eicosanoids (,*)hydroxy)eicosatetraenoic acid and (rostacyclin) unaffected" also #ay contribute to this beneficial effect of ro(ivacaine. 9 Lidocaine failed" however" to inhibit (rostanoid release by hu#an gastric #ucosa in vitro at concentrations less than .*+ -gB#l. 50 Lidocaine ((las#a concentration *),* -#) accelerated the return of bowel function in (atients undergoing radical (rostatecto#y" 51 resulting in a significant shortening of hos(ital stay. LAs (lidocaine ,++ #g bolus intravenously D : #gB#in continuous intravenous infusion" or bu(ivacaine . #gBkg intraabdo#inal installation) also shortened the duration of (osto(erative ileus in (atients undergoing #a9or abdo#inal surgery. 52$53 4eritoneal surgery is associated with release of infla##atory #ediators such as hista#ine" (rostaglandins" and kinins. 52$5 Activation of abdo#inal reflexes resulting in longlasting inhibition of colonic #otility after surgery is likely to be a result of infla##atory reactions in the area undergoing surgery. 1ecause LAs affect the release of infla##atory agents" beneficial effects on bowel function #ay result at least in (art fro# lidocaineIs antiinfla##atory effects. $his hy(othesis is su((orted by the observation that nonsteroidal antiinfla##atory drugs are also effective. 55 $he antiinfla##atory effect of LAs is (rolonged and (ersists after seru# levels have decreased. 5$5! $his #ight ex(lain lidocaineIs effect on bowel function :< h after infusion was discontinued. 52 $aken together" these findings show significant (ro#ise for the use of LAs in the treat#ent of infla##atory bowel disease" as well as in the attenuation of (osto(erative ileus. Effects of LAs on yocardial Infarction and Reperfusion Injury Acute #yocardial infarction is not usually considered an infla##atory disease" but infarction" and (articularly ische#ia)re(erfusion in9ury" is acco#(anied by a significant cardiac infla##atory res(onse. 45 )endothelial interactions occurring during #yocardial ische#ia and re(erfusion are thought to (lay a crucial role" and 45 )derived oxygen #etabolites are i#(ortant in #yocardial in9ury associated with re(erfusion of the ische#ic heart. 57 Activated 45 can induce structural changes in the heart through the action of free radicals and arachidonic acid #etabolites. 58 %n ,C;> 5ullane et al. 59 re(orted that drugs that i#(air 45 function #ay reduce infarct si2e. 7ecent studies have shown that %L)< and %L); are i#(ortant regulators of the infla##atory res(onse in #yocardial infarction" !0 and C*a is suggested as a key #ediator of tissue in9ury in this setting. !1 5oreover" ex(ression of 45 and #onocyte adhesion #olecules and their ligands increases in the acute (hase of #yocardial infarction. !2 %t is not sur(rising that blockade of adhesion #olecules" reducing 45 accu#ulation in the #yocardiu#" exerts significant (rotective effects on #yocardial ische#ia)re(erfusion in9ury in rats. !3 %ntravenous ad#inistration of antibodies against C8,,b)C8,; reduced #yocardial re(erfusion in9ury in an ani#al #odel. ! /i#ilar findings were observed after treat#ent with ,?G)estradiol" which decreased $ ')F levels and reduced intercellular adhesion #olecule),)#ediated binding of 45 to in9ured #yocardiu#" leading to less 45 accu#ulation and subse&uent (rotection against re(erfusion in9ury. !5 Leukotriene synthesis inhibitors also (rovide significant cardio(rotection in #yocardial ische#ia. !! 45 )#ediated endothelial re(erfusion in9ury can be attenuated by 45 de(letion during re(erfusion. !7 Ax(eri#ents in a (orcine #odel of #yocardial ische#ia have shown that lidocaine" either ad#inistered intravenously or (erfused in a retrograde #anner before onset of re(erfusion" (reserved the ische#ic #yocardiu# and reduced infarct si2e after re(erfusion. !8 Lidocaine infusions in dogs reduced infarct si2e" (ossibly by inhibiting release of toxic oxygen #etabolites. !9 %n contrast" de Lorgeril et al. 70 re(orted that" in their dog #odel" lidocaine ((las#a concentration ,: -#) reduced neither infarct si2e nor #yocardial 45 accu#ulation significantly. $hese discre(ancies #ight be caused by differences between the #odels" (articularly the duration of occlusion.

Lidocaine is used for antiarrhyth#ic treat#ent after #yocardial infarction. %t is conceivable that (art of the antiarrhyth#ic effect in this setting is a result of antiinfla##atory effects of lidocaine in areas of #yocardial infarction. Although lidocaine ad#inistration failed to be effective in treating re(erfusion arrhyth#ias in several ex(eri#ental studies in dogs and (igs" 70$71 lidocaine decreased re(erfusion arrhyth#ias caused by free radical)induced enhanced auto#aticity" without effect on reentry arrhyth#ias. 72 LAs and Increased Ris% of Infection An i#(ortant as(ect of the antiinfla##atory (ro(erties of LAs is a (ossible increase in susce(tibility to infections: LA)#ediated de(ression of the 45 oxidative #etabolic res(onse #ay decrease the ability to control bacterial (roliferation. %nvestigations suggest" however" that the re#aining 45 function is sufficient to #ini#i2e the risk. 4eck et al. 38 found that the #icrobicidal function of 45 s fro# (atients receiving lidocaine infusions was only slightly decreased. Although Nroudine et al." 51 who showed that lidocaine infusion has beneficial effects on bowel function in (atients undergoing radical (rostatecto#y" concluded that lidocaine #ight be useful in #a9or abdo#inal surgery" caution see#s warranted in e#(loying LA infusions (intravenously or e(idurally) in surgical (atients with gross bacterial conta#ination of body cavities. %n a letter res(onding to the re(ort of Nroudine et al." 8rage 73 referred to a study by 5acNregor et al." 3! in which five of six rats treated with lidocaine (,.* #gBkg intravenous bolus D +.: #g E kg:3 E #in:3) died within >; h fro# Staphylococcus aureus inoculation (: O ,+= colony) for#ing units intra(eritoneally)" but of six rats that were inoculated with S. aureus but not treated with lidocaine only a single ani#al died. 4owell et al. 7 re(orted increased infection risk if eutectic #ixture of local anesthestics crea# was a((lied to conta#inated wounds. %t a((ears" therefore" that LAs are #ost likely to be beneficial in settings of sterile infla##ation" in which the excessive infla##atory res(onse is a #a9or (athogenic factor. %n contrast" LAs #ight be detri#ental in settings of bacterial conta#ination" in which an un#itigated infla##atory res(onse is re&uired to eli#inate the #icroorganis#s. Local anesthetics" in #illi#olar concentrations" (ossess anti#icrobial (ro(erties in vitro 75$7! and in vivo. 77 Lidocaine (:? ##) inhibits growth of Escherichia coli and Streptococcus pneumoniae but has no effect on S. aureus or Pseudomonas aeruginosa= .M lidocaine (?> ##) inhibits all of these bacteria. 78 /ch#idt and 7osenkran2" 79 utili2ing a larger nu#ber of bacterial (athogens" showed si#ilar results" de#onstrating inhibition of all (athogens exce(t S. aureus and P. aeruginosa. $he #echanis#s behind this antibacterial action are unclear. 80 7ecent investigations suggest that the anti#icrobial activity see#s to be bactericidal rather than bacteriostatic. 81 7ecently" /akuragi et al. 82 showed that (reservative)free bu(ivacaine (>.>).<.+ ##) (ossesses te#(erature) and concentration)de(endent bactericidal activity against #icroorganis#s in the hu#an skin flora. S. aureus was #ore resistant to bactericidal activity of bu(ivacaine than were Staphylococcus epidermidis or E. coli. /uch antibacterial actions" however" are obtained only at high concentrations. 'eld#an et al. 83 observed that low concentrations of bu(ivacaine had" at best" li#ited antibacterial activity and did not inhibit growth of coagulase)negative sta(hylococcus. $hey concluded that LAs are unlikely to (revent" for exa#(le" e(idural catheter)related infections. Only bu(ivacaine concentrations of ; ## or higher a((eared to have antibacterial (ro(erties. Concentrations of LAs in the e(idural environ#ent" are in the #illi#olar range. Although" to our knowledge" no (ublished studies exist" it #ight be (ossible that the antibacterial (ro(erties of e(idural LAs contribute to (revention of e(idural infections= if so" eli#inating LAs fro# e(idural infusions #ight result in a higher infection rate. !igh concentrations of LAs also inhibit viruses. Lsing an in vitro test ((la&ue neutrali2ation test in Hero cells) to study the antiviral action of LAs against her(es si#(lex virus ," 8e A#ici et al. 8 re(orted that anesthetics with inter#ediate (otency such as #e(ivacaine can inhibit viral re(lication by u( to *+M" but only with concentrated solutions (#ore than ,M 3:* ##6) and if a((lied in co#bination with e(ine(hrine. 1u(ivacaine (,*.* ##) also inhibited" but again" without e(ine(hrine the effect was reduced #arkedly. %nhibition was #axi#al with ,M (a((roxi#ately :,)##) solutions. %t is likely that the inhibitory effect is

directed (ri#arily against the virus itself and not (as with #ost antiviral drugs) #ediated by interference with the #echanis#s of cellular re(lication. LAs can exert antiviral activity in a concentration)de(endent #anner. $his effect is influenced by other factors such as os#olarity and (resence of e(ine(hrine ((ossibly a p ! effect)" es(ecially if a less concentrated solution is e#(loyed. 1ecause the antibacterial and antiviral effects of LAs are observed only at high concentrations" antiinfla##atory actions of these co#(ounds at syste#ic levels in theory can increase the risk of infection. $his has not been relevant in the in vivo studies re(orted to date" exce(t in settings of gross bacterial conta#ination. One of the hall#arks of the findings described here is that these co#(ounds can #odulate excessive infla##atory res(onses without significant i#(air#ent of host defenses. $he next section describes the cellular actions underlying this infla##atory #odulation. Effects of LAs on Inflammatory &ells and ediators Effects on Release of Inflammatory ediators Leukotrienes" (articularly L$1>" (lay an i#(ortant role in the early (hase of infla##ation. 85 7eduction of leukotriene release is therefore a #a9or o(tion for #odulating infla##ation. Leukotriene 1>" for#ed in infla##atory cells such as 45 s and #onocytes" is a (otent sti#ulator of 45 activity. %t induces #argination at endothelial cells" degranulation" dia(edesis" and su(eroxide generation and acts synergistically with (rostaglandin A. to enhance vascular (er#eability. %t has a high che#otactic (otency for 45 s (i.e." it is a (otent leukoattractant) in vitro and in vivo. 1locking release of this che#otactic #ediator exerts an antiinfla##atory action" because 45 s no longer are recruited to the infla##atory site. LAs block leukotriene release. In vitro (reincubation of hu#an 45 s or #onocytes with different concentrations of lidocaine or bu(ivacaine (.).+ ## lidocaine and +.>)>.> ## bu(ivacaine) inhibit L$1> release nearly co#(letely. 8! $his #ay ex(lain so#e of the antiinfla##atory effects of the co#(ounds. 1ecause L$1>" in co#bination with (rostaglandin A." induces ede#a for#ation" blockade of L$1> release by LAs #ay ex(lain in (art the beneficial effects of LAs on ede#a for#ation. 30 %nterleukin),F is another infla##atory #ediator" which" acting on its rece(tor on 45 s" sti#ulates (hagocytosis" res(iratory burst" che#otaxis" and degranulation. 7educed release of cytokines such as %L),F therefore also would contribute to an antiinfla##atory effect of LAs. In vitro" a#ide LAs" such as lidocaine and bu(ivacaine" dose)de(endently (lidocaine +..).+.+ ##" bu(ivacaine >>)>">++ -#) inhibit %L),F release in li(o(olysaccharide)sti#ulated hu#an (eri(heral blood #ononuclear cells. 8! Lidocaine also inhibits hista#ine release fro# hu#an (eri(heral leukocytes" cultured hu#an baso(hils" and #ast cells in vitro at concentrations in the high #icro#olar range. 87 %t therefore a((ears that LAs can inhibit the release of several critical infla##atory #ediators= in addition to direct effects on 45 s and #acro(hage function" this #ay be one of the #ain (athways by which they exert their antiinfla##atory effects. Effects of LAs on P N Adhesion Adhesion of 45 s to endotheliu#" if excessive" #ay induce endothelial in9ury" which is #ediated by several adhesion #olecules. One of the #ost i#(ortant for fir# adhesion of 45 to endotheliu# and subse&uent trans#igration (dia(edesis) is C8,,b)C8,;" a #e#ber of the integrin fa#ily. 88 $his rece(tor is ex(ressed constitutively on the surface of nonactivated 45 " but ex(ression increases #arkedly after infla##atory sti#ulation. 1inding of activated 45 to endothelial cells by C8,,b)C8,; increases intracellular (eroxide levels in the endothelial cells" in which reactive oxygen s(ecies can have detri#ental effects. 89 5onoclonal antibodies against C8,,b)C8,; (rotect in vitro against endothelial cell in9ury. 89 In vitro studies have shown a reduction of $ ')F)induced u()regulation of C8,,b)C8,; surface ex(ression on 45 after ro(ivacaine or lidocaine treat#ent. $his #ay contribute to the beneficial in vivo effects of ro(ivacaine on ulcerative colitis" 32 at tissue concentrations (,++):++ -#) obtained after rectal LA ad#inistration. 7eco#binant hu#an granulocyte colony)sti#ulating factor (rhN)C/') (artici(ates in 45 )endothelial interactions by sti#ulating 45 functions and u(regulating ex(ression on 45 s of cellular adhesion #olecules" such as C8,,b)C8,;. Lidocaine (.+ ##)" added to 45 s during incubation with rhN)C/'" abolished the (ri#ing effect of rhN)C/' and inhibited rhN)C/')sti#ulated surface ex(ression of C8,,b.

$he effect was concentration)de(endent (>)>+ ##)" and decreased 45 adherence in vitro. 90 1ecause increases in intracellular Ca1@ concentration (lay a #a9or role in 45 activation" 91 and u(regulation of C8,,b is also Ca1@)de(endent" 92 in vitro inhibition by lidocaine (,> ##) of increases in intracellular Ca1@ concentration 93 #ay be res(onsible for this action. 0hen adhering to surfaces" 45 s flatten out the rounded cell sha(e characteristic for circulating cells. Conversely" rounding of 45 s (revents endothelial adhesion. Low te#(erature" colchicine" and cyclic adenosine #ono(hos(hate (revent 45 s fro# flattening and therefore fro# adhering to surfaces. 7ounding is characteri2ed by cell contraction" synthesis of retraction fibrils" and withdrawal of cell (rocesses. %nhibition of (hagocytosis" lysoso#al en2y#e release" su(eranion (roduction and (ost(hagocytic oxygen consu#(tion all are associated with #arked cell rounding and withdrawal of cell (rocesses. 2!$9 -97 %f 45 s are ex(osed to LAs in vitro (lidocaine ,. ## or tetracaine ,.* ##)" these #or(hologic changes also occur" followed by inhibition of adherence and therefore i#(aired 45 delivery to sites of infla##ation. 98 4erfusion with LA)free #ediu# reverses these effects. 7ounding also occurs after a@ de(letion of or 5g1@ and Ca1@ addition to the #ediu#. 1ecause tetrodotoxin does not affect rounding" the LA effect see#s unrelated to a@ channel inhibition. 7abinovitch and 8e/tefano 9 re(orted that #acro(hages cultured in vitro and incubated with either lidocaine (,. ##) or tetracaine (,.* ##) underwent reversible cell rounding" associated with cell contraction and withdrawal of cell (rocesses. In vitro" lidocaine induces a dose)de(endent reduction of granulocyte adherence= significant effects are obtained with concentrations P ,++ -#. In vivo" bolus in9ection of ..* #gBkg lidocaine in rabbits caused a transient decrease in adherence (to >+M of control) * #in later. 3! Adherence recovered ,* #in after in9ection. Continuous lidocaine infusion (+.: #g E kg:3 E #in:3) after bolus in9ection #aintained this inhibitory effect for the duration of infusion. /i#ilar results were obtained in hu#ans receiving a ,++)#g bolus of lidocaine intravenously for treat#ent of arrhyth#ia. 3! 4eritonitis is acco#(anied by a (rofound increase in 45 adherence and subse&uent delivery into the exudate. %n rabbits" lidocaine (,.* #gBkg bolus" followed by +.: #g E kg:3 E #in:3) #arkedly inhibited both adherence (to .*M of control) and delivery (to .M of control)" #easured < h after induction of (eritonitis and initiation of lidocaine infusion. 3! %n this ex(eri#ent" lidocaine treat#ent caused a #ore than ,+)fold larger inhibition of infla##ation than did #ethyl(rednisolone (.) to :)kg rabbits were given ,*)#g doses of the de(ot for# subcutaneously twice at ?)day intervals" and ,): days after the second dose sterile (eritonitis was induced). %n the ha#ster cheek (ouch (re(aration" ro(ivacaine (,++ -#) #arkedly inhibits L$1>)induced 45 adhesion in (ostca(illary and larger venules. $his #ay be caused by an effect on 45 rolling or fir# adhesion. 32 7eduction of 45 rolling #ay result in (art fro# alterations in blood flow and in (art fro# effects on 45 )endothelial interactions. 32 Local anesthetics decrease the ability of 45 s to adhere to surfaces. As a result" one would antici(ate a significant effect on 45 accu#ulation at the site of infla##ation. Effects of LAs on P N igration 5igration of 45 s is a key event during the infla##atory res(onse. LidocaineIs inhibitory effect on 45 #igration has been re(orted by several investigators" using both in vitro and in vivo #odels. 99-101 !a##er et al. 99 showed in vitro that lidocaine (>).+ ##) concentration)de(endently inhibits hu#an 45 #etabolis# and rando# #obility" with co#(lete i##obili2ation of 45 s occurring in the (resence of .+ ##. 8ickstein et al. 102 re(orted that" in vitro" ex(osure to ,),++ -# lidocaine inhibits #acro(hage #igration. 8estruction of the functional integrity of cytoskeletal structures" 103 interference with Ca1@) de(endent cellular (rocesses" 10 and interaction with #e#brane li(ids" causing changes in stability and fluidity of the #e#brane" #ay contribute to the observed effect of the co#(ound. 102 Effects of LA on P N Accumulation 0ound healing re&uires that a large nu#ber of 45 s #igrate to an in9ured area. Affects of local ad#inistration of LAs on wound healing (rocesses are of s(ecial interest" because these drugs often are in9ected into tissue for (ain relief after surgery. /tudies on this to(ic have" however" yielded contradictory conclusions. /o#e in vivo investigations have de#onstrated delayed wound healing" 105 no effects" 10! or even i#(roved wound healing 107 after LA infiltration.

Ariksson et al. 101 investigated the effects of lidocaine on 45 accu#ulation in a wound" using an in vivo rat #odel. %nfla##ation was induced by i#(lantation of a titaniu# cha#ber close to the (eritoneu#. 4retreat#ent of the wound with ,+ #g lidocaine reduced the accu#ulation of 45 in the wound area co#(ared with saline)treated rats. Che#ilu#inescence in the lidocaine grou( was reduced #arkedly" indicating su((ression of #etabolic res(onsiveness of 45 . 5acNregor et al. 3! re(orted that in rats 45 accu#ulation during (eritonitis is su((ressed by lidocaine (,.* #gBkg bolus followed by infusion of +.: #g E kg:3 E #in:3 for the duration of the ex(eri#ent). /cott et al. 108 found that lidocaine" at #icro#olar concentrations" i#(airs accu#ulation and adherence of 45 s in an in vivo canine #odel. $hese findings #ay be ex(lained by inhibition of 45 adherence (and therefore inhibition of #igration)" 3!$100$109 or a direct inhibitory effect on #otility and #igration of 45 s. 3!$99$100 %n addition" it is conceivable that LAs inhibit che#oattractant release by i#(airing cell #etabolis#. 8!$9!$99$101 %t a((ears that LAs reduce the ability of 45 s to #igrate to the site of infla##ation by interference with the critical ste(s of adhesion and #igration. $he result is decreased 45 accu#ulation. Effects of LAs on P N Priming $he (ri#ing (rocess can be described as a (otentiated res(onse of 45 s after (revious ex(osure to (ri#ing agents" such as $ ')F" (latelet)activating factor" %L);" li(o(olysaccharide" or granulocyte) #acro(hage colony)sti#ulating factor. 4ri#ing is a key regulatory #echanis# of 45 function and see#s to (lay a (ivotal role in the oversti#ulation of infla##atory (athways" which then induces tissue da#age rather than (rotect the host. As such" the (rocess is being investigated intensively" but #echanis#s are as yet (oorly understood. An excellent overview of the (atho(hysiologic conse&uences and underlying #echanis#s of 45 (ri#ing was (ublished in ,CC; by Condliffe et al. 110 $he effects of LAs on 45 (ri#ing have not been investigated in detail. 0e have shown in vitro that lidocaine blocks (ri#ing of 45 s by lyso(hos(hatidic acid in a concentration)de(endent #anner (%C*+ @ , -#). 111 %n contrast to other LA actions on these signaling syste#s" the LAs acted at an extracellular site= the non(er#eable lidocaine analog QR:,> had effects si#ilar to those of lidocaine. %t is (ossible that inhibition of (ri#ing contributes to the antiinfla##atory actions of LAs" and in (articular su((resses the deleterious effects of the uncontrolled" overactive res(onse of infla##atory cells to a sti#ulating agent. $his #ight ex(lain how LAs can decrease tissue da#age without significantly inhibiting 45 functions re&uired for host defense. A84!)oxidase activity" Ca1@" (rotein kinase C" (hos(holi(ase 8" and (hos(hatidylinositol):)kinase are likely to be involved in the (ri#ing (rocess. %n other settings" inhibition of A84!)oxidase activity" Ca1@" transients and (rotein kinase C have been described for several LAs 112 such that the co#(ounds #ight be antici(ated to affect (ri#ing. 93$113$11 Affects of LAs on (hos(holi(ase 8 and (hos(hatidylinositol) :)kinase to our knowledge have not been (ublished. Interactions of LAs with P N priming re'uire more in!estigation( Effects of LAs on P N )ree Radical and $ranule En*yme Release Activated 45 s generate light (che#ilu#inescence)" which can be #easured as an indicator of #etabolic activity" that is" free radical generation. Although so#e researchers have &uestioned the usefulness of this #ethodology for investigation of 45 function" because the nature of detected oxidants is uncertain" che#ilu#inescence is a co##only used" sensitive" noninvasive techni&ue to #easure reactive oxidant (roduction by 45 . In vitro" lidocaine and bu(ivacaine inhibit lu#inol)a#(lified che#ilu#inescence concentration)de(endently (%C*+ @ >)* ## for lidocaine and ,.>)..+ ## for bu(ivacaine" de(ending on the #anner of activation). 8!$38 7e(orts of effects of lower concentrations have been contradictory: /o#e investigators have re(orted no or only a slight i#(air#ent of che#ilu#inescence by LAs in vitro, 115117 but !attori et al. 5 de#onstrated in vitro su((ression of 45 free radical generation by eight different LAs in a concentration)de(endent #anner (+., and ,+ ##). $he inhibitory effect correlated with the (artition coefficient for each drug= that is" the #ore li(id)soluble LAs were #ore (otent inhibitors of free radical (roduction. $etrodotoxin" veratridine" and a#iloride hydrochloride were tested for their abilities to affect free radical generation by hu#an 45 s. 1ecause none of these co#(ounds showed any inhibitory effects" the underlying #echanis# of LA action is unlikely to be a@ influx blockade. 5

Cederhol# et al. 118 studied in vitro effects of ro(ivacaine" bu(ivacaine" lidocaine" #e(ivacaine" and (rilocaine on both intra) and extracellular (roduction of oxygen #etabolites in hu#an 45 s. LAs (+.*) .++.+ -#) caused a s#all but statistically significant decrease in che#ilu#inescence res(onse. 4rilocaineIs inhibitory effect on extracellular release was acco#(anied by an enhanced intracellular activity. $his #akes this drug (articularly noteworthy" because excessive extracellular free radical release #ay cause tissue da#age" and increased intracellular activity i#(roves anti#icrobial (ro(erties. 118 /tudies on surgical wounds in rats confir#ed the effects of LAs on free radical release in vivo. 101 $he inhibitory effect of LAs on 45 affects not only the (roduction of O. : but also the generation of hydrogen (eroxide and hydroxyl radical. 5ikawa et al. 119 re(orted in vitro that LAs at concentrations of +.,),.. ## decrease release of reactive oxygen s(ecies such as O. :" !.O." and O!:. LAs do not scavenge the reactive oxygen s(ecies generated but rather inhibit the ability of 45 s to (roduce the#. 119 Effects of LAs on P N Lysosomal En*yme Release Anti#icrobial activity results in (art fro# release of lysoso#al en2y#es by 45 s. $herefore 4eck et al. 38 investigated in vitro the effects of ; ## lidocaine on lyso2y#e and #yelo(eroxidase release and co#(ared these effects with the ability of lidocaine)treated 45 to kill E. coli. Lidocaine significantly i#(aired release of both en2y#es and reduced the ca(ability of killing E. coli fro# C* to ?+M. $hese findings were confir#ed in vitro for lidocaine and tetracaine. 95 Affects of LA on 45 itric Oxide Neneration itric oxide (lays #ulti(le" at ti#es contradictory" roles in the infla##atory (rocess. 1ecause nitric oxide synthase inhibitors enhance in vivo the nu#ber of 45 s adherent to endothelial cells of #esenteric vessels" 120 increased nitric oxide (roduction has an antiinfla##atory action. itric oxide attenuates tissue in9ury during endotoxe#ia and se(sis in vivo. 121 %n contrast" over(roduction of nitric oxide by the inducible nitric oxide synthase (i O/) ex(ressed in #acro(hages or neutro(hils has been i#(licated in the (athogenesis of se(tic shock or tissue in9ury against the host itself leading to #ulti(le organ failure. /u((ression of nitric oxide over(roduction by i O/ inhibitors occasionally acts advantageously. $he i O/ inhibitor a#inoguanidine successfully attenuates endotoxin)induced acute lung in9ury in vivo. 122 In vivo blockade of $ ' (by $ ')binding (rotein) and nitric oxide (by a#inoguanidine) decreases 45 che#otaxis and se&uestration and attenuates acute lung infla##ation induced by ische#ia and re(erfusion of lower extre#ity. 123 $he effects of LAs on nitric oxide #etabolis# has not been described in detail. In vitro" LAs enhance N) for#yl)#ethionyl)leucyl)(henylalanine) or (horbol #yristate acetate)induced nitric oxide generation in hu#an 45 s. 12 $his #ay contribute to the (rotective effects of LAs" although it see#s unlikely to be a #a9or (athway. Effects of LAs on acrophages 5acro(hages are (ivotal in the infla##atory res(onse. As the (ri#ary defense against in9urious agents" they generate significant a#ounts of cytokines and other infla##atory #ediators. %n an in vitro study of hu#an alveolar #acro(hages" tetracaine and lidocaine were reversible" dose)de(endent inhibitors of oxidative #etabolis# (oxygen consu#(tion and free radical release). $his inhibition was associated with cell rounding and occurred at LA concentrations as (resent in effluents recovered during broncho(ul#onary lavage (.),< ##). 2! Ogata et al. 125 re(orted in vitro that LAs (,+ ##) reversibly inhibited (hagocytosis by #acro(hages" in a concentration) and p !)de(endent #anner. $etracaine exerted the largest and (rocaine the s#allest effect. 4hagocytosis by #onocytes in vitro also is inhibited by lidocaine. 12! Lidocaine" in concentrations (*++ -#) routinely in9ected into tissue" inhibits (hagocytosis and #etabolis# of hu#an 45 s in vitro. 9! 5acro(hage functions such as cytokine release" res(iratory burst and (hagocytosis are sensitive to intracellular p ! changes" regulated by vacuola)ty(e !@)translocating adenosine tri(hos(hatase and the a@)!@ exchanger ( !A). LAs bind to !A" 127 and lidocaine inhibits !A in hu#an 45 s in vitro. 93 Lidocaine also dose)de(endently slowed intracellular p ! recovery and su((ressed (horbol #yristate acetate)induced res(iratory burst in rabbit alveolar #acro(hages in vitro" without decreasing #etabolic activity or viability of the #acro(hages. %nhibition of the intracellular p ! regulatory #echanis# #ay

contribute to effects of LAs on alveolar #acro(hage function. $hese findings su((ort the hy(othesis that the effect of lidocaine on (hagocytosis and other #acro(hage (rocesses #ight result in (art fro# to an inhibitory effect on !A. 128 echanisms of Action A variety of actions of LAs on infla##atory cells have been described" #any of which suggest that LAs #ight #odulate the infla##atory res(onse in various disease states. 5ost in vitro studies re&uire concentrations of LAs above the clinically relevant range=in vivo studies of the sa#e or si#ilar (heno#ena often de#onstrate effects at clinically feasible concentrations. $he reasons for this discre(ancy are unknown. $he issue is (articularly re#arkable because one would antici(ate that larger free LA concentrations would be available in #any (rotein)free in vitro solutions" as co#(ared with in vivo situations. %t #ay be that the #ulti(le #olecular targets of LAs allow (otentiating interactions in vivo that cannot be attained in a si#(lified in vitro #odel. Alternatively" the #ore (rolonged ex(osure to LAs during in vivo investigations #ay (lay a role. 0e found that" in Xenopus oocytes" sensitivity of thro#boxane A. and lyso(hos(hatidic acid signaling to lidocaine and bu(ivacaine increased #ore than five)fold if incubation ti#es were extended fro# ,+ #in to ,. h. 129 Lnfortunately" virtually nothing is known about the s(ecific #olecular #echanis#s involved in these effects. %n #any instances" a@ channel blockade can be ruled out" either because in vitro a@ channels are not detectable in the cells under study or because in vivo LAs induce effects at concentrations #uch lower than those re&uired for a@ channel blockade. /everal #echanis#s have been suggested ("ig# 2)" but only a few targets have been described in #olecular detail. LA interactions with N (rotein)cou(led rece(tors are an area of active investigation" because #ost #ediators involved in the infla##atory (rocess signal through rece(tors of this class. 0e have shown that LAs inhibit signaling of several N (rotein)cou(led rece(tors #ediating infla##atory res(onses (lyso(hos(hatidic acid 130$131 and thro#boxane A.)" 132 as well as #, #uscarinic acetylcholine rece(tors. 'unctional findings using lyso(hos(hatidic acid and (latelet)activating factor in Xenopus oocytes were confir#ed in hu#an neutro(hils. 111 One co##on target on several N (rotein) cou(led signaling (athways is the cou(led N& (rotein. /elective knockdown of N& eli#inates LA sensitivity of lyso(hos(hatidic acid signaling= knockdown of No is without effect. 133 0e have shown that the signaling (athway downstrea# of the N (rotein is not involved in the LA effect. 130$131 %nhibitory effects of the co#(ounds on !A are described elsewhere here. %nteractions of LA with 4KC signaling have been described" 93 but very little s(ecific infor#ation is available. $his area clearly deserves further research.

'ig. .. /che#atic overview of several suggested #echanis#s of local anesthetic action on infla##atory cells. cA54 @ cyclic adenosine #ono(hos(hate= N4C)7s @ N (rotein)cou(led rece(tors= A84! @ nicotina#ide adenine dinucleotide (hos(hate= !A @ a@)!@ exchanger= 4KC @ (rotein kinase C. Conclusions Clear evidence exists" in vitro as well as in vivo" for antiinfla##atory (ro(erties of LAs. Affects on 45 #ediator and free radical release" as well as #igration to the site of action" a((ear #ost i#(ortant. $he #olecular #echanis#s underlying these effects are (oorly delineated. Of (articular relevance is the difference in concentrations re&uired to achieve effects on infla##atory cells in vitro versus #uch lower in vivo concentrations. Clinical use of LA/ for the ex(licit (ur(ose of #odulating the excessive infla##atory res(onse #ay be feasible. $reat#ent of ulcerative colitis with to(ical ro(ivacaine is one exa#(le. %t see#s (ossible that so#e of the beneficial effects of e(idural ad#inistration of LAs (which leads to blood levels close to those attained after intravenous infusion) #ay be caused by antiinfla##atory effects of circulating LAs. Affects on (rolonged (ain and hy(ercoagulation are exa#(les. %n those (atients not able or willing to receive intra) or (osto(erative e(idural analgesia" intravenous infusion of LAs could be considered in order to #odulate (osto(erative infla##atory res(onses. %n the setting of bacterial conta#ination" however" there is an increased risk of infection. 'urther research should be directed (ri#arily in two areas. 'irst" we need to gain a detailed understanding of the #echanis#s of action of LAs on the infla##atory syste#. /tructure)function studies are (articularly essential" because they can lead to the develo(#ent of novel co#(ounds. /econd" #ore well)designed clinical studies should be (erfor#ed" to assess whether the effects of LAs observed in cells and in ani#als also can be a((lied to clinical (ractice. $he authors thank 4rof. 8r. #ed. A. 5artin" 7u(recht)Karls)LniversitJt !eidelberg" Ner#any" for his su((ort and C. 8i'a2io" 5.8." 4h.8." 4rofessor of Anesthesiology" 8e(art#ent of Anesthesiology" Lniversity of Hirginia !ealth /ciences Center" Charlottesville" Hirginia" for critically reviewing the #anuscri(t.
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S 4har#acol Ax( $her ,CC?= .;:: *C)<* ::. Alexander '" 5athieson 5" $eoh K!" !uval 0H" Lelcuk /" Haleri C7" /he(ro 8" !echt#an !1: Arachidonic acid #etabolites #ediate early burn ede#a. S $rau#a ,C;>= .>: ?+C),. :>. 7obson 5C" 8el 1A" !eggers S4: $he effect of (rostaglandins on the der#al #icrocirculation after burning" and the inhibition of the effect by s(ecific (har#acological agents. 4last 7econstr /urg ,C?C= <:: ?;,)? :*. Cassuto S" ellgard 4" /tage L" Sonsson A: A#ide local anesthetics reduce albu#in extravasation in burn in9uries. A nesthesiology ,CC+= ?.: :+.)?

:<. 5acNregor 77" $horner 7A" 0right 85: Lidocaine inhibits granulocyte adherence and (revents granulocyte delivery to infla##atory sites. 1lood ,C;+= *<: .+:)C :?. /tewart NS" 7itchie 0N" Lynch 47: Henous endothelial da#age (roduced by #assive sticking and e#igration of leukocytes. A# S 4athol ,C?>= ?>: *+?):. :;. 4eck /L" Sohnston 71 Sr" !orwit2 L8: 7educed neutro(hil su(eroxide anion release after (rolonged infusions of lidocaine. S 4har#acol Ax( $her ,C;*= .:*: >,;).. :C. akagawara 5" !irokata U" Uoshitake S: Affects of anesthetics on the su(eroxide releasing activity of hu#an (oly#or(honuclear leukocytes. 5asui ,C;*= :>: ?*>)C >+. 8e#ling 7!: 0ound infla##atory #ediators and #ultisyste# organ failure. 4rog Clin 1iol 7es ,C;?= .:<A: *.*):? >,. Casey LC" Ar#strong 5C" 'letcher S7" 7a#well 40: Lidocaine increases (rostacyclin in the rat. 4rostaglandins ,C;+= ,C: C??);> >.. Na#se 7" !ol2er 4" Le#beck ': 8ecrease of substance 4 in (ri#ary afferent neurones and i#(air#ent of neurogenic (las#a extravasation by ca(saicin. 1r S 4har#acol ,C;+= <;: .+?),: >:. Sohns 7A" 8i'a2io CA" Longnecker 8A: Lidocaine constricts or dilates rat arterioles in a dose)de(endent #anner. A nesthesiology ,C;*= <.: ,>,)> >>. 5artinsson $: 7o(ivacaine inhibits seru#)induced (roliferation of colon adenocarcino#a cells in vitro. S 4har#acol Ax( $her ,CCC= .;;: <<+)> >*. Asklin 1" Cassuto S: %ntravesical lidocaine in severe interstitial cystitis. Case re(ort. /cand S Lrol e(hrol ,C;C= .:: :,,). ><. 19orck /" 8ahlstro# A" Ahl#an !: $o(ical treat#ent of ulcerative (roctitis with lidocaine. /cand S Nastroenterol ,C;C= .>: ,+<,)?. >?. Arlander A" Ost A" /tahlberg 8" Lofberg 7: 7o(ivacaine gel in active distal ulcerative colitis and (roctitis: A (har#acokinetic and ex(loratory clinical study. Ali#ent 4har#acol $her ,CC<= ,+: ?:);, >;. 19orck /" 8ahlstro# A" Sohansson L" Ahl#an !: $reat#ent of the #ucosa with local anaesthetics in ulcerative colitis. Agents Actions ,CC.= s(ecial nu#ber:C<+)?. >C. 5artinsson $" !aegerstrand A" 8alsgaard CS: Affects of ro(ivacaine on eicosanoid release fro# hu#an granulocytes and endothelial cells in vitro. %nfla## 7es ,CC?= ><: :C;)>+: *+. Noel 7K" $avares %A" ellgard 4" Sonsson A" Cassuto S" 1ennett A: Affect of lignocaine on eicosanoid synthesis by (ieces of hu#an gastric #ucosa. S 4har# 4har#acol ,CC>= ><: :,C).+ *,. Nroudine /1" 'isher !AN" Kauf#an 74" 4atel 5S" 0ilkins LS" 5ehta /A" Lu#b 48: %ntravenous lidocaine s(eeds the return of bowel function" decreases (osto(erative (ain" and shortens hos(ital stay in (atients undergoing radical retro(ubic (rostatecto#y. Anesth Analg ,CC;= ;<: .:*)C *.. 7i#back N" Cassuto S" $ollesson 4O: $reat#ent of (osto(erative (aralytic ileus by intravenous lidocaine infusion. Anesth Analg ,CC+= ?+: >,>)C *:. 7i#back N" Cassuto S" 'axen A" !ogstro# /" 0allin N" $ollesson 4O: Affect of intra)abdo#inal bu(ivacaine instillation on (osto(erative colonic #otility. Nut ,C;<= .?: ,?+)* *>. 8i 7osa 5" Niroud S4" 0illoughby 8A: /tudies on the #ediators of the acute infla##atory res(onse induced in rats in different sites by carrageenan and tur(entine. S 4athol ,C?,= ,+>: ,*).C **. Cheng N" Cassissi C" 8rexler 4N" Hogel /1" /ninsky CA" !ocking 54: /alsalate" #or(hine" and (osto(erative ileus. A# S /urg ,CC<= ,?,: ;*); *<. 8ickstein 7" Kire#id9ian)/chu#acher L" /tot2ky N: Affect of lidocaine on the function of i##unoco#(etent cells: %%. Chronic in vivo ex(osure and its effects on #ouse ly#(hocyte activation and ex(ression of i##unity. %##uno(har#acology ,C;*= C: ,.?):C *?. /i#(son 4S" Lucchesi 17: 'ree radicals and #yocardial ische#ia and re(erfusion in9ury. S Lab Clin 5ed ,C;?= ,,+: ,:):+ *;. /e#b AN" Utrehus K" Haage S" 5yklebust 7: Cardiac in9ury by activated leukocytes: Affect of cyclooxygenase and li(oxygenase inhibition evaluated by electron #icrosco(ical #or(ho#etry. S 5ol Cell Cardiol ,CC<= .;: :,,).+ *C. 5ullane K5" 7ead " /al#on SA" 5oncada /: 7ole of leukocytes in acute #yocardial infarction in anestheti2ed dogs: 7elationshi( to #yocardial salvage by anti)infla##atory drugs. S 4har#acol Ax( $her ,C;>= ..;: *,+).. <+. eu#ann 'S" Ott %" 5arx " Luther $" Kenngott /" Nawa2 5" Kot2sch 5" /cho#ig A: Affect of hu#an reco#binant interleukin)< and interleukin); on #onocyte (rocoagulant activity. Arterioscler $hro#b Hasc 1iol ,CC?= ,?: ::CC)>+* <,. Hakeva A4" Agah A" 7ollins /A" 5atis LA" Li L" /tahl NL: 5yocardial infarction and a(o(tosis after #yocardial ische#ia and re(erfusion: role of the ter#inal co#(le#ent co#(onents and inhibition by anti)C* thera(y. Circulation ,CC;= C?: ..*C)<? <.. 5eisel /7" /ha(iro !" 7adnay S" eu#an U" Khaskia A7" Nruener " 4au2ner !" 8avid 8: %ncreased ex(ression of neutro(hil and #onocyte adhesion #olecules L'A), and 5ac), and their ligand %CA5), and HLA)> throughout the acute (hase of #yocardial infarction: (ossible i#(lications for leukocyte aggregation and #icrovascular (lugging. S A# Coll Cardiol ,CC;= :,: ,.+)* <:. Nu#ina 7S" el /chult2 S" Uao V" Kenny 8" 0arltier 8C" ew#an 4S" Nross NS: Antibody to (lateletBendothelial cell adhesion #olecule), reduces #yocardial infarct si2e in a rat #odel of ische#ia)re(erfusion in9ury. Circulation ,CC<= C>: ::.?) ::

<>. /i#(son 4S" $odd 7'" 'antone SC" 5ickelson SK" Nriffin S8" Lucchesi 17: 7eduction of ex(eri#ental canine #yocardial re(erfusion in9ury by a #onoclonal antibody (anti)5o," anti)C8,,b) that inhibits leukocyte adhesion. S Clin %nvest ,C;;= ;,: <.>)C <*. /&uadrito '" Altavilla 8" /&uadrito N" Ca#(o N5" Arlotta 5" Arcoraci H" 5inutoli L" /errano 5" /aitta A" Ca(uti A4: ,?1eta)oestradiol reduces cardiac leukocyte accu#ulation in #yocardial ischae#ia re(erfusion in9ury in rat. Aur S 4har#acol ,CC?= ::*: ,;*)C. <<. 7ossoni N" /ala A" 1erti '" $esta $" 1uccellati C" 5olta C" 5uller)4eddinghaus 7" 5aclouf S" 'olco NC: 5yocardial (rotection by the leukotriene synthesis inhibitor 1AU R,++*: i#(ortance of transcellular biosynthesis of cysteinyl)leukotrienes. S 4har#acol Ax( $her ,CC<= .?<: ::*)>, <?. /ch#idt 'AS" 5ac8onald 5S" 5ur(hy CO" 1rown 05" Nott S4" Nuyton 7A: Leukocyte de(letion of blood cardio(legia attenuates re(erfusion in9ury. Ann $horac /urg ,CC<= <.: ,<C,)< <;. Lee 7" itta $" /ch#id 7A" /chuessler 71" !arris K5" Nay 0AS: 7etrograde infusion of lidocaine or L)arginine before re(erfusion reduces #yocardial infarct si2e. Ann $horac /urg ,CC;= <*: ,:*:)C <C. Lesnefsky AS" Han1enthuysen K5" 5c5urtry %'" /hikes 7!" Sohnston 71" !orwit2 L8: Lidocaine reduces canine infarct si2e and decreases release of a li(id (eroxidation (roduct. S Cardiovasc 4har#acol ,C;C= ,:: ;C*)C+, ?+. de Lorgeril 5" 7ousseau N" 1as#ad9ian A" Latour SN: Lignocaine in ex(eri#ental #yocardial infarction: failure to (revent neutro(hil accu#ulation and ventricular fibrillation and to reduce infarct si2e. Cardiovasc 7es ,C;;= ..: >:C)>< ?,. 1ergey SL" ocella K" 5cCallu# S8: Acute coronary artery occlusion)re(erfusion)induced arrhyth#ias in rats" dogs and (igs: antiarrhyth#ic evaluation of &uinidine" (rocaina#ide and lidocaine. Aur S 4har#acol ,C;.= ;,: .+*),< ?.. Kabell N" /cherlag 1S" !o(e 77" La22ara 7: 8ifferential effect of lidocaine on re)entry and enhanced auto#aticity. A# S Cardiol ,C;+= >*: />?> ?:. 8rage 5: Caution in the use of lidocaine infusion in the surgical (atient. Anesth Analg ,CC;= ;?: ,.,: ?>. 4owell 85" 7odehaever N$" 'ores#an 4A" !ankins CL" 1ellian K$" Vi##er CA" 1ecker 8N" Adlich 7': 8a#age to tissue defenses by A5LA crea#. S A#erg 5ed ,CC,= C: .+*)C ?*. 7avin CA" Lati#er S5" 5atsen S5: %n vitro effects of lidocaine on anaerobic res(iratory (athogens and strains of !e#o(hilus influen2ae. Chest ,C??= ?.: >:C)>, ?<. 7osenberg 4!" 7enkonen OH: Anti#icrobial activity of bu(ivacaine and #or(hine. A nesthesiology ,C;*= <.: ,?;)C ??. Conte 1A" Laforet AN: $he role of the to(ical anesthetic solutions on bronchial secretions during bronchosco(y. Angl S 5ed ,C<.= .<?: C*?)C ?;. 0einstein 54" 5adera2o A" $ilton 7" 5aggini N" Quintiliani 7: 'urther observations on the anti#icrobial effects of local anesthetic agents. Curr $her 7es Clin Ax( ,C?*= ,?: :<C)?> ?C. /ch#idt 75" 7osenkran2 !/: Anti#icrobial activity of local anesthetics: lidocaine and (rocaine. S %nfect 8is ,C?+= ,.,: *C?)<+? ;+. 'a2ly 1a2a2 1/" /alt 0N: Local anaesthetics as antibacterial agents: effects on cellular res(iration and the leakage of cyto(las#ic constituents. 5icrobios ,C;:= :?: ,:C)>C ;,. /akuragi $" %shino !" 8an K: 1actericidal activity of clinically used local anesthetics on /ta(hylococcus aureus. 7eg Anesth ,CC<= .,: .:C)>. ;.. /akuragi $" %shino !" 8an K: 1actericidal activity of (reservative)free bu(ivacaine on #icroorganis#s in the hu#an skin flora. Acta Anaesthesiol /cand ,CC;= >.: ,+C<)C ;:. 'eld#an S5" Cha(in)7obertson K" $urner S: 8o agents used for e(idural analgesia have anti#icrobial (ro(ertiesT 7eg Anesth ,CC>= ,C: >:)? ;>. 8e A#ici 8" 7a#aioli '" Ceriana 4" 4ercivalle A: Antiviral activity of local anaesthetic agents. S Anti#icrob Che#other ,CC<= :?: <:* ;*. /a#uelsson 1" 8ahlen /A" Lindgren SA" 7ou2er CA" /erhan C : Leukotrienes and li(oxins: /tructures" biosynthesis" and biological effects. /cience ,C;?= .:?: ,,?,)< ;<. /inclair 7" Ariksson A/" Nret2er C" Cassuto S" $ho#sen 4: %nhibitory effects of a#ide local anaesthetics on sti#ulus) induced hu#an leukocyte #etabolic activation" L$1> release and %L), secretion in vitro. Acta Anaesthesiol /cand ,CC:= :?: ,*C)<* ;?. Uanagi !" /ankawa !" /aito !" %ikura U: Affect of lidocaine on hista#ine release and Ca.D #obili2ation fro# #ast cells and baso(hils. Acta Anaesthesiol /cand ,CC<= >+: ,,:;)>> ;;. Arfors KA" Lundberg C" Lindbo# L" Lundberg K" 1eatty 4N" !arlan S5: A #onoclonal antibody to the #e#brane glyco(rotein co#(lex C8,; inhibits (oly#or(honuclear leukocyte accu#ulation and (las#a leakage in vivo. 1lood ,C;?= <C: ::;)>+ ;C. 'u9ita !" 5orita %" 5urota /: A (ossible #echanis# for vascular endothelial cell in9ury elicited by activated leukocytes: A significant involve#ent of adhesion #olecules" C8,,BC8,;" and %CA5),. Arch 1ioche# 1io(hys ,CC>= :+C: <.)C C+. Ohsaka A" /a9on9i K" /ato " %gari S: Local anesthetic lidocaine inhibits the effect of granulocyte colony)sti#ulating factor on hu#an neutro(hil functions. Ax( !e#atol ,CC>= ..: ><+)< C,. Ohsaka A" /aito 5" /u2uki %" 5iura U" $akaku '" Kitagawa /: 4horbol #yristate acetate (otentiates su(eroxide release and #e#brane de(olari2ation without affecting an increase in cyto(las#ic free calciu# in hu#an granulocytes sti#ulated by the che#otactic (e(tide" lectins and the calciu# iono(hore. 1iochi# 1io(hys Acta ,C;;= C>,: ,C):+

C.. 1erger 5" 1irx 8L" 0et2ler A5" OI/hea SS" 1rown AS" Cross A/: Calciu# re&uire#ents for increased co#(le#ent rece(tor ex(ression during neutro(hil activation. S %##unol ,C;*= ,:*: ,:>.); C:. !aines KA" 7eib#an S" Callegari 4A" Abra#son /1" 4hili(s 57" 0eiss#ann N: Cocaine and its derivatives blunt neutro(hil functions without influencing (hos(horylation of a >?)kilodalton co#(onent of the reduced nicotina#ide)adenine dinucleotide (hos(hate oxidase. S %##unol ,CC+= ,>>: >?*?)<> C>. 7abinovitch 5" 8e/tefano 5: Cell to substrate adhesion and s(reading: %nhibition by cationic anesthetics. S Cell 4hysiol ,C?*= ;*: ,;C)C: C*. Noldstein %5" Lind /" !offstein /" 0eiss#ann N: %nfluence of local anesthetics u(on hu#an (oly#or(honuclear leukocyte function in vitro: 7eduction of lysoso#al en2y#e release and su(eroxide anion (roduction. S Ax( 5ed ,C??= ,><: >;:)C> C<. Cullen 1'" !aschke 7!: Local anesthetic inhibition of (hagocytosis and #etabolis# of hu#an leukocytes. A nesthesiology ,C?>= >+: ,>.)< C?. icolson NL" /#ith S7" 4oste N: Affects of local anesthetics on cell #or(hology and #e#brane)associated cytoskeletal organi2ation in 1AL1B:$: cells. S Cell 1iol ,C?<= <;: :C*)>+. C;. 7abinovitch 5" 8e/tefano 5S: Cell sha(e changes induced by cationic anesthetics. S Ax( 5ed ,C?<= ,>:: .C+):+> CC. !a##er 7" 8ahlgren C" /tendahl O: %nhibition of hu#an leukocyte #etabolis# and rando# #obility by local anaesthesia. Acta Anaesthesiol /cand ,C;*= .C: *.+): ,++. /chreiner A" !o(en N: Adhesion and loco#otion of hu#an leukocytes in vitro= i#(ortance of (rotein coating= effect of lidocaine" ethanol and endotoxin. Acta 4athol 5icrobiol /cand C ,C?C= ;?: :::)>+ ,+,. Ariksson A/" /inclair 7" Cassuto S" $ho#sen 4: %nfluence of lidocaine on leukocyte function in the surgical wound. A nesthesiology ,CC.= ??: ?>); ,+.. 8ickstein 7" Kire#id9ian)/chu#acher L" /tot2ky N: Affect of lidocaine on (roduction of #igration inhibitory factor and on #acro(hage #otility: %n vitro ex(osure of guinea (ig ly#(hocytes and #acro(hages. S Leukocyte 1iol ,C;>= :<: <.,):. ,+:. 4oste N" 4a(ahad9o(oulos 8" icolson NL: Local anesthetics affect trans#e#brane cytoskeletal control of #obility and distribution of cell surface rece(tors. 4roc atl Acad /ci L / A ,C?*= ?.: >>:+)> ,+>. Hol(i 5" /ha" A(stein 45" Andrenyak 85" 'einstein 51: Local anesthetics" #e(acrine" and (ro(ranolol are antagonists of cal#odulin. 4roc atl Acad /ci L / A ,C;,= ?;: ?C*)C ,+*. 8avies 1" Nuyuron 1" !usa#i $: $he role of lidocaine" e(ine(hrine" and fla( elevation in wound healing after che#ical (eel. Ann 4last /urg ,CC,= .<: .?:); ,+<. Hasseur 41" 4aul !A" 8ybdal " Cru#ley L: Affects of local anesthetics on healing of abdo#inal wounds in rabbits. A# S Het 7es ,C;>= >*: .:;*); ,+?. Kanta S" Ko(acova L" 4atockova 5" 1artos ': Affect of carbanilate local anesthetics on granulation tissue for#ation. 4ol S 4har#acol 4har# ,C;>= :<: <*C)<: ,+;. /cott 18" /hasby 85" $o#anek 7S" Kieso 7A" /eabold SA" 4onto SA" Kerber 7A: Lidocaine and dextran sulfate inhibit leukocyte accu#ulation but not (ostische#ic contractile dysfunction in a canine #odel. A# !eart S ,CC:= ,.*: ,++.),, ,+C. Niddon 81" Lindhe S: %n vivo &uantitation of local anesthetic su((ression of leukocyte adherence. A# S 4athol ,C?.= <;: :.?):; ,,+. Condliffe A5" Kitchen A" Chilvers A7: eutro(hil (ri#ing: 4atho(hysiological conse&uences and underlying #echanis#s. Clin /ci ,CC;= C>: ><,)?, ,,,. 'ischer LN" Conrad 1" Kru## 1" !oll#ann 50" 8urieux 5A: $i#e)de(endent attenuation by lidocaine of res(iratory burst in hu#an neutro(hils (ri#ed with lyso(hos(hatic acid. Anesth Analg .+++= C+: />+* ,,.. %rita K" 'u9ita %" $akeshige K" 5inaka#i /" Uoshitake S: Cinchocaine and a#ethocaine inhibit activation and activity of su(eroxide (roduction in hu#an neutro(hils. 1r S Anaesth ,C;<= *;: <:C)>* ,,:. Kai $" ishi#ura S" Kobayashi /" $akahashi /" Uoshitake S" Kanaide !: Affects of lidocaine on intracellular Ca.D and tension in airway s#ooth #uscle. A nesthesiology ,CC:= ?;: C*>)<* ,,>. $o#oda 5K" $suchiya 5" Leda 0" !irakawa 5" Ltsu#i K: Lidocaine inhibits sti#ulation)cou(led res(onses of neutro(hils and (rotein kinase C activity. 4hysiol Che# 4hys 5ed 57 ,CC+= ..: ,CC).,+ ,,*. /i#iniak $" 0ysocki !" Heit A" 5aurer !7: $he effect of selected antiarrhyth#ic drugs on neutro(hil free oxygen radicals (roduction #easured by che#ilu#inescence. 1asic 7es Cardiol ,CC,= ;<: :**)<. ,,<. 0hite %0" Nelb A0" 0exler !7" /tiller C7" Keown 4A: $he effects of intravenous anaesthetic agents on hu#an neutro(hil che#ilu#inescence. Can Anaesth /oc S ,C;:= :+: *+<),, ,,?. !yvonen 45" Kowolik 5S: 8ose)de(endent su((ression of the neutro(hil res(iratory burst by lidocaine. Acta Anaesthesiol /cand ,CC;= >.: *<*)C ,,;. Cederhol# %" 1rihei# N" 7utberg !" 8ahlgren C: Affects of five a#ino)a#ide local anaesthetic agents on hu#an (oly#or(honuclear leukocytes #easured by che#ilu#inescence. Acta Anaesthesiol /cand ,CC>= :;: ?+>),+ ,,C. 5ikawa K" Aka#atsu !" ishina K" /higa 5" 5aekawa " Obara !" iwa U: %nhibitory effect of local anaesthetics on reactive oxygen s(ecies (roduction by hu#an neutro(hils. Acta Anaesthesiol /cand ,CC?= >,: *.>); ,.+. Kubes 4" /u2uki 5" Nranger 8 : itric oxide: An endogenous #odulator of leukocyte adhesion. 4roc atl Acad /ci L / A ,CC,= ;;: ><*,)* ,.,. ishida S" 5cCuskey 7/" 5c8onnell 8" 'ox A/: 4rotective role of O in he(atic #icrocirculatory dysfunction during endotoxe#ia. A# S 4hysiol ,CC>= .<?: N,,:*)>,

,... 5ikawa K" ishina K" $a#ada 5" $akao U" 5aekawa " Obara !: A#inoguanidine attenuates endotoxin)induced acute lung in9ury in rabbits. Crit Care 5ed ,CC;= .<: C+*),, ,.:. $assio(oulos AK" !aki# $/" 'inck C5" 4edoto A" !odell 5N" Landas /K" 5cNraw 8S: eutro(hil se&uestration in the lung following acute aortic occlusion starts during ischae#ia and can be attenuated by tu#our necrosis factor and nitric oxide blockade. Aur S Hasc Andovasc /urg ,CC;= ,<: :<)>. ,.>. 5a#iya K" $o#oda 5K" Adashige K" Leda 0" 5anabe 5: Local anesthetics enhance nitric oxide (roduction by hu#an (eri(heral neutro(hils. 4hysiol Che# 4hys 5ed 57 ,CC*= .?: ,,,)C ,.*. Ogata K" /hinohara 5" %noue !" 5iyata $" Uoshioka 5" Ohura K: Affects of local anesthetics on rat #acro(hage (hagocytosis. i((on Uakurigaku Vasshi ,CC:= ,+,: *:); ,.<. Okuno /" oda !" Kugi#iya $" /aion9i K: $he influence of local anesthetics on hu#an leukocyte functions studied by #icro whole blood collection and flowcyto#etry. 5asui ,CC<= >*: :,?).* ,.?. !ille 1: Local anesthetics: !ydro(hilic and hydro(hobic (athways for the drug)rece(tor reaction. S Nen 4hysiol ,C??= <C: >C?)*,* ,.;. 1idani A" !e#ing $A: Afects of lidocaine on cytosolic (! regulation and sti#ulus)induced effector functions in alveolar #acro(hages. Lung ,CC?= ,?*: :>C)<, ,.C. 0iec2orek K" !oll#ann 50" Nraf 15" 5artin A" 8urieux 5A: Local anesthetics inhibit lyso(hos(hatidate signaling ti#e) and (! de(endent. Anaesthesiologie and %ntensiv#edi2in .+++= >,: :;* ,:+. ietgen N0" Chan CK" 8urieux 5A: %nhibition of lyso(hos(hatidate signaling by lidocaine and bu(ivacaine. A nesthesiology ,CC?= ;<: ,,,.)C ,:,. /ullivan L5" !oene#ann C0" Arledge SA5" 8urieux 5A: /ynergistic inhibition of lyso(hos(hatidic acid signaling by charged and uncharged local anesthetics. Anesth Analg ,CCC= ;;: ,,,?).> ,:.. !oene#ann C0" 4odranski $" Lo 1" Uanovitch 5" 8urieux 5A: Local anesthetic effects on thro#boxane A. signaling. A nesthesiology ,CC;= ;C: A;;< ,::. !oll#ann 50" 1erger A" 'ischer LN" 8urieux 5A: Lyso(hos(hatidate and #uscarinic #, rece(tor signaling is #ediated by different N)(rotein al(ha subunits. Anesth Analg .+++= C+: />.< ,:>. Olschewski A" !e#(el#ann N" Hogel 0" /afronov 1H: 1lockade of a@ and K@ currents by local anesthetics in the dorsal horn neurons of the s(inal cord. Anesthesiology ,CC;= ;;: ,?.)C ,:*. Aguilar S/" Criado 5" 8e 7oberts A: %nhibition by local anesthetics" (hentol)a#ine and (ro(ranolol of 3!6Quinyclydinyl ben2ylate binding to central #uscarinicrece(tors. Aur S 4har#acol ,C;+= <;: :,?).< ,:<. 1ittencourt AL" $akahashi 7 : 5a2indol and lidocaine are antinocice(tives in the #ouse for#alin #odel: involve#ent of do(a#ine rece(tor. Aur S 4har#acol ,CC?= ::+: ,+C),: ,:?. /2ekeres L" 4a(( SN: Antiarrhyth#ic co#(ounds. 4rog 8rug 7es ,C<;= ,.: .C.):<C ,:;. 5orris $" A((bly 7: 7etardation of wound healing by (rocaine. 1r S /urg ,C;+= <?: :C,). ,:C. Chva(il 5" !a#eroff /4" OI8ea K" 4eacock AA: Local anesthetics and wound healing. S /urg 7es ,C?C= .?: :<?)?, ,>+. 8rucker 5" Cardenas A" Ari2ti 4" Halen2uela A" Na#boa A: Ax(eri#ental studies on the effect of lidocaine on wound healing. 0orld S /urg ,CC;= ..: :C>)? ,>,. Ariksson A/" /inclair 7" Cassuto S" $ho#sen 4: %nfluence of lidocaine on leukocyte function in the surgical wound. Anesthesiology ,CC.= ??: ?>); ,>.. Cooke A8" 1owcock /A" Lloyd 5S" 4ilcher 5': %ntravenous lignocaine in (revention of dee( venous thro#bosis after elective hi( surgery. Lancet ,C??= .: ?C?)C ,>:. 5odig S" 1org $" Karlstro# N" 5ari(uu A" /ahlstedt 1: $hro#boe#bolis# after total hi( re(lace#ent: role of e(idural and general anesthesia. Anesth Analg ,C;:= <.: ,?>);+ ,>>. !enny C4" Odoo# SA" $enCate S0" $enCate 7S'" Osterhoff '" 8abhoiwala '" /ih %L: Affects of extradural bu(ivacaine on the he#ostatic syste#. 1r S Anaesth ,C;<= *;: :+,)* ,>*. $u#an KS" 5cCarthy 7S" 5arch 7S" 8eLaria NA" 4atel 7H" %vankovich A8: Affects of e(idural anesthesia and analgesia on coagulation and outco#e after #a9or vascular surgery. Anesth Analg ,CC,= ?:: <C<)?+> ,><. Luostarinen H" Avers !" Lyytikainen 5$" /cheinin" 0ahlen A: Antithro#botic effects of lidocaine and related co#(ounds on laser)induced #icrovascular in9ury. Acta Anaesthesiol /cand ,C;,= .*: C),, ,>?. /tewart NS: Antithro#botic activity of local anesthetics in several canine #odels. 7eg Anesth ,C;.= ?: ;C)C< ,>;. 'einstein 5N" 'iekers S" 'raser C: An analysis of the #echanis# of local anesthetic inhibition of (latelet aggregation and secretion. S 4har#acol Ax( $her ,C?<= ,C?: .,*).; ,>C. Kohrs 7" !oene#ann C0" 'eirer " 8urieux 5A: 1u(ivacaine inhibits whole blood coagulation in vitro. 7eg Anesth 4ain 5ed ,CCC= .>: :.<):+ ,*+. 1org $" 5odig S: 4otential anti)thro#botic effects of local anesthetics due to their inhibition of (latelet aggregation. Acta Anaesth /cand ,C;*= .C: ?:C)>. ,*,. Odoo# SA" /turk A" 8okter 40C" 1ovill SN" $enCate S0" Oosting S: $he effects of bu(ivacaine and (i(ecoloxylidide on (latelet function in vitro. Acta Anesthesiol /cand ,C;C= ::: :;*); ,*.. Nibbs 5" /ear S0: Affect of ketorolac" bu(ivacaine" and low)dose he(arin on thro#belastogra(hic variables in vitro. 1r S Anaesth ,CC*= ?*: .?):+

,*:. /teinbach A1: Alteration by xylocaine (lidocaine) and its derivatives of the ti#e course of the end (late (otential. S Nen 4hysiol ,C<;= *.: ,>>)<, ,*>. eher A" /teinbach S!: Local anaesthetics transiently block currents through single acetylcholine)rece(tor channels. S 4hysiol ,C?;= .??: ,*:)?< ,**. 7uff 7L: $he kinetics of local anesthetic blockade of end)(late channels. 1io(hys S ,C;.= :?: <.*):, ,*<. 'relin C" Higne 4" La2dunski 5: 1ioche#ical evidence for (har#acological si#ilarities between al(ha)adrenorece(tors and voltage)de(endent a@ and Ca@@ channels. 1ioche# 1io(hys 7es Co##un ,C;.= ,+<: C<?)?: ,*?. 4alade 4$" Al#ers 0: /low calciu# and (otassiu# currents in frog skeletal #uscle: their relationshi( and (har#acologic (ro(erties. 4flugers Arch ,C;*= >+*: C,),+, ,*;. Nraha# S!" 5aher S7" 7obinson /A: $he effect of cocaine and other local anesthetics on central do(a#inergic neurotrans#ission. S 4har#acol Ax( $her ,CC*= .?>: ?+?),? ,*C. Nranger 4" 1iton 1" 'aure C" Hige R" 8e(oortere !" Nraha# 8" Langer /V" /catton 1" Avenet 4: 5odulation of the ga##a)a#inobutyric acid ty(e A rece(tor by the antie(ile(tic drugs carba#a2e(ine and (henytoin. 5ol 4har#acol ,CC*= >?: ,,;C)C< ,<+. ord#ark S" 7yd&vist 1: Local anaesthetics (otentiate NA1A)#ediated Cl: currents by inhibiting NA1A u(take. eurore(ort ,CC?= ;: ><*); ,<,. Craviso NL" 5usacchio S5: Co#(etitive inhibition of stereos(ecific o(iate binding by local anesthetics in #ouse brain. Life /ci ,C?*= ,<: ,;+:); ,<.. 'airhurst A/" 0hittaker 5L" Ahlert 'S: %nteractions of 8<++ (#ethoxyvera(a#il) and local anesthetics with rat brain al(ha)adrenergic and #uscarinic rece(tors. 1ioche# 4har#acol ,C;+= .C: ,**)<. ,<:. 'ields SV" 7oeske 07" 5orkin A" Ua#a#ura !%: Cardiac #uscarinic cholinergic rece(tors: bioche#ical identification and characteri2ation. S 1iol Che# ,C?;= .*:: :.*,); ,<>. Li U5" 0ingrove 8A" $oo !4" 5arnerakis 5" /ti#son A7" /trichart2 N7" 5aggio SA: Local anesthetics inhibit substance 4 binding and evoked increases in intracellular Ca1@. Anesthesiology ,CC*= ;.: ,<<)?: ,<*. Liu K" Adachi " Uanase !" Kataoka K" Arai $: Lidocaine su((resses the anoxic de(olari2ation and reduces the increase in the intracellular Ca1@ concentration in gerbil hi((oca#(al neurons. Anesthesiology ,CC?= ;?: ,>?+); ,<<. Chen S" Adachi " Liu K" agaro $" Arai $: %#(rove#ent of ische#ic da#age in gerbil hi((oca#(al neurons by (rocaine. 1rain 7es ,CC;= ?C.: ,<).: ,<?. /churr A" /(ears 1" 7eid K!" 0est CA" Ad#onds !LS" 7igor 15: Lidocaine de(resses syna(tic activity in the rat hi((oca#(al slice. Anesthesiology ,C;<= <>: *+,): ,<;. 'u9itani $" Adachi " 5iya2aki !" Liu K" aka#ura U" Kataoka K" Arai $: Lidocaine (rotects hi((oca#(al neurons against ische#ic da#age by (reventing increase of extracellular excitatory a#ino acids: a #icrodialysis study in 5ongolian gerbils. eurosci Lett ,CC>= ,?C: C,)> ,<C. 5uir SK" Lyeth 1N" !a## 7S" Allis A': $he effect of acute cocaine or lidocaine on behavioral function following fluid (ercussion brain in9ury in rats. S eurotrau#a ,CC*= ,.: ;?)C? ,?+. !a## 7S" $e#(le 58" 4ike 17" Allis A': $he effect of (ostin9ury ad#inistration of (olyethylene glycol)con9ugated su(eroxide dis#utase ((egorgotein" 8is#utec) or lidocaine on behavioral function following fluid)(ercussion brain in9ury in rats. S eurotrau#a ,CC<= ,:: :.*):. ,?,. 8as KC" 5isra !4: Lidocaine: a hydroxyl radical scavenger and singlet oxygen &uencher. 5ol Cell 1ioche# ,CC.= ,,*: ,?C);* ,?.. Astru( S" /orensen 45" /orensen !7: %nhibition of cerebral oxygen and glucose consu#(tion in the dog by hy(other#ia" (entobarbital" and lidocaine. Anesthesiology ,C;,= **: .<:); ,?:. 1rown 7!" 7obbins 0" /taats 4" !irsh#an C: 4revention of bronchoconstriction by an orally active local anesthetic. A# S 7es(ir Crit Care 5ed ,CC*= ,*,: ,.:C)>: ,?>. Nroeben !" /ilvanus 5$" 1este 5" 4eters S: 1oth intravenous and inhaled lidocaine attenuate reflex bronchoconstriction but at different (las#a concentrations. A# S 7es(ir Crit Care 5ed ,CCC= ,*C: *:+)* ,?*. Nroeben !" 'oster 05" 1rown 7!: %ntravenous lidocaine and oral #exiletine block reflex bronchoconstriction in asth#atic sub9ects 3see co##ents6. A# S 7es(ir Crit Care 5ed ,CC<= ,*>: ;;*); ,?<. Nroeben !" /chwalen A" %rsfeld /" /tieglit2 /" Li(fert 4" !o(f !1: %ntravenous lidocaine and bu(ivacaine dose) de(endently attenuate bronchial hy(erreactivity in awake volunteers. Anesthesiology ,CC<= ;>: *::)C ,??. 8unst 5 " 5argolin K" !orak 8: Lidocaine for severe hiccu(s. Angl S 5ed ,CC:= :.C: ;C+), ,?;. eeno $A" 7osenow AC: %ntractable hiccu(s. Consider nebuli2ed lidocaine. Chest ,CC<= ,,+: ,,.C):+ ,?C. /hio#i U" aga#ine $" 'u9iki " !irano /" aito U" /hibasaki !" !on9o %: $innitus re#ission by lidocaine de#onstrated by auditory)evoked #agnetoence(halogra#: a (reli#inary re(ort. Acta Otolaryngol ,CC?= ,,?: :,)> Citing Articles Time+dependent Inhi"ition of $ Protein+coupled Receptor ,ignaling "y Local Anesthetics( Anesthesiology. ,++(>):;*.);<+" A(ril .++>. !oll#ann" 5arkus 0. 5.8." 4h.8. W= !erroeder" /usanne 5.8. D= Kur2" Katrin /. 5.8. D= !oene#ann" Christian 0. 5.8. DD= /true#(er" 8an9a 5.8. 3/6= !ahnenka#(" Klaus 5.8. 3/6= 8urieux" 5arcel A. 5.8." 4h.8. 3BB6

Lidocaine Enhances $-alpha.i Protein )unction( Anesthesiology. CC(*):,+C:),,+," ove#ber .++:. 1enkwit2" Claudia 5.8. W= Narrison" Sa#es C. 4h.8. D= Linden" Soel 4h.8. DD= 8urieux" 5arcel A. 5.8." 4h.8. 3/6= !oll#ann" 5arkus 0. 5.8." 4h.8. 3BB6 Lidocaine Attenuates onocyte &hemoattractant Protein+/ Production and &hemota0is in 1uman onocytes: Possi"le echanisms for Its Effect on Inflammation( Anesthesia X Analgesia. C?(*):,:,.),:,<" ove#ber .++:. Li" Chi)Uuan 58" 5/ W= $sai" Chien)/ung 58 D= !su" 4ing)Ching 5/ D= Chueh" /heau)!uei 4h8 DD= 0ong" Chih)/hung 58" 4h8 W= !o" /hung)$ai 58" 5/ W Effects of Antidepressants on $ Protein+coupled Receptor ,ignaling and 2ia"ility in 3enopus lae!is 4ocytes( Anesthesiology. CC(>):C,,)C,?" October .++:. /tru#(er" 8an9a 5.8. WD= 8urieux" 5arcel A. 5.8." 4h.8. DD3/63BB6= $roster" 1arbara 5./. Y= !ahnenka#(" Klaus 5.8. W= Hitan" Cristina 5./. WW= den 1akker" Christel N. DD= !oll#ann" 5arkus 0. 5.8." 4h.8. DDDD The Effects of ,5+6+7 R586+7 and Racemic 9upi!acaine on Lysophosphatidate+Induced Priming of 1uman Neutrophils( Anesthesia X Analgesia. C?(>):,+*:),+*;" October .++:. !oll#ann" 5arkus 0. 58" 4h8 WDDD= Kur2" Katrin 5/ WD= !erroeder" /usanne 5/ WD= /true#(er" 8an9a 58 DDD= !ahnenka#(" Klaus 58 DD= 1erkel#ans" oud /. 5/ D= den 1akker" Christel N. 5/ D= 8urieux" 5arcel A. 58" 4h8 DDD Need for Additional &ontrol in ,tudies of Epidural 4utcome( Anesthesiology. C;(<):,*..),*.:" Sune .++:. Sohnson" 5ichael A. 5.8." 4h.8. Effects of Antidepressants on )unction and 2ia"ility of 1uman Neutrophils( Anesthesiology. C;(<):,:*<),:<." Sune .++:. /tru#(er" 8an9a 5.8. WD= 8urieux" 5arcel A. 5.8." 4h.8. DD= !oll#ann" 5arkus 0. 5.8." 4h.8. 3/6= $roster" 1arbara Y= den 1akker" Christel N. WW= 5arcus" 5arco A. A. 5.8." 4h.8. DD Local Anesthetics odulate Neuronal &alcium ,ignaling through ultiple ,ites of Action( Anesthesiology. C;(*):,,:C),,><" 5ay .++:. Ru" 'ang 4h.8. W= Naravito)Aguilar" Vayra 1./. D= 7ecio)4into" As(eran2a 4h.8. DD= Vhang" Sin 5.8. 3/6= S. 1lanck" $ho#as S. 5.8." 4h.8. 3BB6 Effects of ,ystemic Local Anesthetics on Perioperati!e Ischemia Reperfusion ay 9e 9eneficial( Anesthesia X Analgesia. C<(.):<.C" 'ebruary .++:. !ar#on" 8o#inic 55ed/ci" 'CA7C/%= Lan" 0ei 51 Inhi"ition of ammalian $' Protein )unction "y Local Anesthetics( Anesthesiology. C?(<):,>*,),>*?" 8ece#ber .++.. !oll#ann" 5arkus 0. 5.8." 4h.8. W= 5c%ntire" 0illia# A. 5.8." 4h.8. D= Narrison" Sa#es C. 5.8." 4h.8. DD and= 8urieux" 5arcel A. 5.8." 4h.8. 3/6 Inhi"ition of ammalian $' Protein )unction "y Local Anesthetics( Anesthesiology. C?(<):,>*,),>*?" 8ece#ber .++.. !oll#ann" 5arkus 0. 5.8." 4h.8. W= 5c%ntire" 0illia# A. 5.8." 4h.8. D= Narrison" Sa#es C. 5.8." 4h.8. DD and= 8urieux" 5arcel A. 5.8." 4h.8. 3/6 The Effect of Local Anesthetics and Amitriptyline on Pero0idation In 2i!o in an Inflammatory Rat odel: Preliminary Reports( Anesthesia X Analgesia. C*(>):CC.)CC<" October .++.. Leduc" Christine 5/c W"= Nentili" 5arc A. 58" 5/c DD"= Astebe" Sean)4ierre 58" 4h8 DD"= Le Corre" 4ascal 4har#8" 4h8 D"= 5oulinoux" Sac&ues)4hili((e 58" 4h8 W"= Acoffey" Claude 58 3/6 No!el local anaesthetics and no!el indications for local anaesthetics( Current O(inion in Anaesthesiology. ,>(<):?>,)?>C" 8ece#ber .++,. !oll#ann" 5arkus 0. a"b= 8urieux" 5arcel A. a= Nraf" 1ernhard 5. b Local Anesthetic Effects on Priming and Acti!ation of 1uman Neutrophils( Anesthesiology. C*(,):,,:),.." Suly .++,. !oll#ann" 5arkus 0. 5.8. W= Nross" Ariane D= Selacin" iko D= 8urieux" 5arcel A. 5.8." 4h.8. DD