Exhibit F
`
`A co111parison of the anti-infla111n1atory properties of intranasal
`corticosteroids and antihista1nines in allergic rhinitis
`
`P, H, Howarth
`i/N:,,1r, ,,; R~,,,,a:;.:.c;ry.C"" ,,,v, :';1<M::,:':;r ~"~'J\J'i
`R~,M":!\ t:n',~n,l'! <JI $,s::H1:,m;.:i,,,~ ''''*""'' Hi
`l,!;;d<:1;;. ~n,ni',~:nr.•t&n. l.:1':
`
`i\Ikrg:ic rbfoitis rnani.fost~ itsrlf dinica.lly drn~ to !JK'. lo,:al rekas~ of rmxfaitors
`frqni u,:1ivat1cxl c:dL, \V.itbin the na~a.1 nuK:(Js,i. Tn;atmcnt stni:tq:;ks ai.m ritfo:r l(1
`reduce the ,Jf(.Tt!, of 1hcs,~ m1x!iaklrs on the s1~11,;orv ncu.rnl a11,I ya.s<:ular end
`onrn.ns ... nr to redu,x~ Hie tissue accmnufali.on of 0:1/ activ;itcd cells that g:rnernte
`th;;ll, c:nrticosktn1ds (!llcr</ene at ,l !llff!lti~~r of s!cps i11 ihc infbi:nmat,;~y
`pathway, and,. hy rl'dudng Hw release of cytoki.ncs a.n.d ch{'mokines, .in.hi.bi! cell
`1\ ... c1·nitme;1t <rnd activntion. Thc,~c dfocts are evident both ht vin:, ,ln{l #t rimi.
`Whik: antihistamines also hah: s<1rne anti-inihrnirnato•ry d:f~"'CtS in riito, Hicst
`t-c(Jlii:r<.) higkr C(HK:eniratio11s tba.n with corti<:osten,ids and a:r~~ not con:si.sknt.ly
`rcproduccd 11:1 rh./,. fo additkm, aHlNugh anlihtsWmincs and corticostet,)ids
`mig.ht appear to have eo:rnpkmcntary mecbrnis1m; of act1011, clinical trial:-\
`snggcsl l!rnt thd:r cnddministrntion docs not confor any additkn,al lnng-terrn
`bendlts cmnpc.u-cd with thal ad1icved ·with conicosternids afonc, Topical
`c.oftic,)stcrnids an:: thernfo:t{: lhe ptdcncd anti-inl'km:urnikiry thernpy for
`persistent alkrgk rhinitis.
`
`l ntrod u cti on
`Allergic rhinitis. is the di.nical nmnifosiat1on of the local
`release:, within the nasal mu.:xisa, of iwdfa:torn fro:m
`adivatcd iniliu:nmatory cclh (1 }. Inmmnohistodwtr11('.al
`sludit'.S of nasal biopsi('.s tak('.n from patie11t:-; with
`a.llergk rhi11itis shmv an accrnm,lation within the
`epithelium ()/' eosinophils, ba~opliib, and m,rnt cells
`{2~4\ which are believed to lx: the primary dfoctor cdfa
`in this condition, whik nasal lavage reveab devatcd
`kvcis or co:-;inophil cationi..: protein and tryptase in
`seasonal and rx'rerinlal illlergic rhinitis, indicativ<.: ofcdl
`activMion (5),
`Treatment hw alkrgk rhinitis is directed (O\:Vrrrd
`reducing either the tissue accunrulation d' these
`at:tiv,ltd c~Hs or the end-organ d1e-c1s of the rek.a:-;1;.'.d
`mcdiatorn. Tltc two mm,t :i1nportant -::lass(~s of piu.irmH·
`,tims Hf~.
`cn!ogic agn1b used
`to achieve Hies(~
`respectively, topical. corticosteroids aml. Hi~anti.h:ista~
`mi:nc~, \Vhik Hi-antihistamines arc dearly effective i11
`relieving symptoms, particularly those m,sociatcd with
`sensory nuarat stimulation, it has bcrn propos"d that
`manv drnus within this elm,:; h..w(: mor(", extcmfrvc
`,:i:.ttk;·ns, m~1difying {he iI1flam1rn1tory proc(:~~ in ,1.ddi(cid:173)
`tion to inhibiifag the H 1-reccptor-n1<:dia.kd cnd~organ
`cffeds uf hhtarn:inc, As such. l-11-<wtihisfan:iincs might
`be potentially consickrcd an alt,~rnative prophylactic
`therni,v to topical (:onko~t(~roids in rhinitis. To address
`tlw
`this c~msidt~ration, Uris paper brid1y rcvkws
`in
`111.ed1anisms 11)\mlv~d
`in
`,).invays
`inlfomnrntkm
`
`6
`
`alk:rgic rhinitis and exan:1i:nC$ the in 1.'itro and in vivo
`cvide11ec for the rnkvant anti~inflammatory potemial
`and effocts of these tW() £bsses of phannacologi('.
`agents.
`
`A!!argic airways inflammation
`The mct:ior pathways involved m ufk,rgic airways
`inlhmnmtion «re sh1;nvn in Fig. I. In udditim1 to IgE(cid:173)
`dcpcndcnt activati011 of mast cells inducing; mediat,)r
`rdca5e, activated mast cells and ·r cdfa prodnec '1Tl.1
`.::vtokines, \Ybich, in turn, activate both endothelial a:nd
`CfYiHidial i.::c:Hs { !). EndoH1,dial activation 1c;:;.uHs in the
`expression nf endothdiaJ adhesion mokcuks ,;uth a;:;
`intercdlufar ad!K:sfrin mok'<:nk-1 (IC'i\l\-l-1) and, lllOR:
`importantly.
`adhesion molccuk-1
`vaseufar
`r.:cll
`(VCAJ\:l-1 }, \1/hik both these adhd:imi mokcuks are
`potentially involved in tis:rnt-ceH rt':Cruitmcnt (6} the
`i ntcracfam between VCAM:. I a11d the ligand VLA-4 is
`more ;;;pedfo.:' fnr alkrgie i11flam:matlo:n, bdng involved
`not only in cosinophil adherence but abrl in basophi1
`and lynrph(1.::yte endothdial interaction~ .. lb(: dircc.t-:.d
`;mivcinent of i.::db thrnugh the ii~~uc toward th,~ mi:~al
`lumen, once iranscndothdbl n:iig.rntion has taken phtcc,
`is dependent upon cd.l-cdl eon tact and thdoea! rckasc
`of t:hemokincs, Epithdial activation is a,·,soc:ialcd -wilh
`the generation <md rcka:<se (if a. nmnher ofi:hcn:wkinc:-. ~
`;;;uch as rctdated on activation, iwrm&l T-ccl1cxpri~sscd
`and s1x:r;ied (RANTES), mi;crnphagc inGanunawry
`prokin (J\UP)-1 ':i., nwnocyt,~ d:1emot:wtk: pr(rtein
`
`

`

`ass<.i<.:iakd \'iiith ..::ell re,Tnitrucnt and activation, and,
`llltimat(:.>h', di:nk--a.l di.seas.:; expn;ssi011.
`The i2l{1cocorti<::·oid rnokcu!c enk1i- the tdl and hinds
`to th-:: ~ytoplasmic g!utocorticoid receptor, displacing
`the ass1xiatcd beat-shock pnitcins, The glucocorticoid/
`thtc9cortic.01d tt.-x::cptor cornpkx can either bind to the
`tra11scr:iptir:,n factors themselves within the cytoplasm,
`thereby preventing their interaction with DNA and thus
`indirectly blocking their effects on gene e;-;pr-C$Sion, or
`trnnslocate to the mxkus and bind &s a dimer w the
`DNA 'thi.;; direct intcrai:.:tion •Vith DNA modifies gene
`trnns(:riptkm, down.ri:::guhting the prodnctkm or pro(cid:173)
`i:nlfamruatnry prntdus c•r np-R:gnlating th<c: gcncrntkln
`Qf anti-inl1amntatory ones. 'This latt<c:r action may
`rcquirnhighcr conccntnrtions than the dov,tH'egulatory
`activitv. C.xticosteroid~ thus hnvc b<ith direct ,md
`i.t1dinx~t cfiz:ch,
`inhibiting;
`trnnseriptinn fad\)r•
`in
`it1duecd. gent~ expression.
`
`Studies ,.vith .::ort.kostern.ids in rifto have ~hown !hat
`this dass of drug has potent cm.>t:ts <m 'T cells, inhibiting
`their stimulated proliforation and synthc~is of Ti:h
`cvt okines at kwv concen trntions { 1 l -13}. ln thi:-; n:;,ped.
`fl~rtica.sone propionate is
`the · nwst poknt of Hi(:
`currently availabk topical cnrtic()Skr<Jids, having an
`K\ 0 (inhihitory con<..<::ntration producing a 50'':>/, rcdi.JC(cid:173)
`.,
`,
`··1
`.
`·1
`·1
`!' 11i··l(l -,..1·
`l
`) ,
`lion m i. ic :,tun tl atc<. response.1 m t. K'. range n l l
`.1v.
`( L\ 14). 1n addition tu thi:-. inhibitory cfF.:ct on T cdh,
`floti.cas.one prnpinnate inhibits tht: rekasc of lL-4, lL-6,
`lL~S. ,:md TNF~·:x from stimnlated ma:'lt tdb with an
`IC~,, of < I n:M (LS}. The IC.s:n for inhibiting tl:!C reka~c
`ofiNF-::t and GM-CS.F from ihe 1-itlmulated epithelium
`are (U
`:md l.O nl\-·L .re::;pectivdy (16)- Epitlldium(cid:173)
`scncrated lL-6 aftd n .. -8 arl'.: kss ;,cnsftivc to the dkcts
`;;f fhitita.S(tnc. w:ith lC<;,, {)f 5 and 10 nl\•t respectively
`(l6\
`
`.
`
`.,.,
`
`.
`
`h'guni' .'. lnJfo<1ncc nfflutic;,i.~;:.)r,;i pr,)piorii.l.t-3 ()fi mrii,,osal lL-4
`mRNA in M,a! bk,psk1, in seasQt1al alkrgic dtinil.is (Cm«cn:>n
`d. ;,1. !VD-
`
`7
`
`{l\·1CPH, i:nterleukh1-E (IL-S), and eotaxin - which are
`dwmoattractants for cosinophils, ma:,;t cells, lympho(cid:173)
`cytes. m:utrop.hi!s, a.ml basophih, and direct
`the
`inigratiou of tlwsc cells toward the epith;;.,liurn and
`na;~,l airwa.y lmncn (h Epithdial activation can thu~
`account for the srx:cific accurnulaJion (lf rnast C,~lk,
`eositwphib, bas<;.phils, and T cd!s withiti the cplthdimn
`in alkrn:k rhiniHs.
`rt f<:J:hw..-~ ih:at therapy which reduces either the
`c:,,;prcss:i;,)n of these cbcnmki11cs or the cytokincs
`assoda.kd ·with cndothdial and cpiLhdial m.:,tivation
`vli!l diminhh the recruitment or tJK'-SC dkctor cells rmd
`thus decrease the availability of mcdiatoxs to induce
`symptom cxprcssixm.
`Cvwkine and dwmokirtt <..~xprc::.sion is regulated by
`tran;.::ription Tactorn such as intdcar factor kappa H
`CNF,d:li. A .. P-L and NF-AT {8}. In the unactivated cdl.
`!rnnscfir:Hion riu::tor:-, cxH 111 an itrndiv,~ form, and cdl
`sti!nubti<Wl resnlis in their activati,)n with a rew!tant
`upregulated ex:prcssion of 0ytokit1c and . d1cmokine
`rn<.'.SM:T1ger RNA (rnRN/\), for t~.xampk, NFi..:13 exists
`,is a diml'.:r bound t,J a.n inhibitory prntcin, l kapp,iB
`(hd3}; within the cytoplasn-i {9J; When exposed to an
`activation stimufo~, phosphorylation nf Uw inhibitory
`pn}lein kad~
`to h)ss of binding,
`,u1d
`the d.inw.r
`dlssocia tcs from th(: inhibitrn:y protein and trn:nslocaks
`to the nw:.leus, Once there., it interacts with the DNA,
`resulting in a dirccti.:'.d increase in gene txprcssk.H1 and
`Hpn:,gul;tim1 c,fspcciik cytokinc (c,g,.JL-1 at1d TNF-::-t.)
`and chcm,Jk\ne (e.g., RA.NTES and cota:s.in) syntl:K~is.
`The tran;;;cription foctor NFKl~ afao contn.ifa
`the
`svnthesb of adh(:sion rnd<:ci1ks frm::h
`:1s VC/\l\,f- l)
`a\id c;1zvmcs (such a:; inducibk nitric oxide l':ynthasc
`[iNOSJ) -~if 1.·dcvancc to i1lkrgk natal inifamrnation,
`
`Corticosremids
`Cortk:Qstc:roids ac;t by rnqdifying the ability nr trnn,
`scription fictors. to UJ:Htgufate grne cxpre~sion (10).
`Thus, by acting very early in the in!1ammatory pathway,
`cnrtt,;qstrroid:;; <,:an pn~,-(~nt
`the {'.Hsc;<1de ()f ;;:,·e1Hs
`
`

`

`Howarth
`
`Topical corticosteroid ih<::rnpy inlfo(:nces mtll1Y a~pects
`of tht a.llcrgk mucosa! resrKmse, ~lrn::h of the published
`literature e<m,x:rnt flutkas(,nc propionate,. and, to a
`lesser extent, budcsonide. Flutkasonc propfom1.te sig(cid:173)
`mficantly blunts the seasonal increa:;;ef, in the expresskm
`of mR NA for both ILA (Fig. 2) (17} and JL-5 (18), in
`na.sa1 mucosa! hklpsfos in se:asonaJ aJkrgic rhinitis. ln
`addition, pwphylactlc treatment with lfotkasonc pro(cid:173)
`pionate, as compared to plw.:oebo, pr<::vcnts the perkel(cid:173)
`luJar <c.ixpression of the .activated ,md stx:rded form of
`1L-4 (as demonstrn.ted l:rv the number of imrminoreac(cid:173)
`tivc 3H4 + ('.dk) on nasai"mliC()Sal miistcel!s in :seH$Orl~tl
`rhirlitis (Fig. 3} (19) .. Thus, fl:utiea.sonc propionate
`downregt11a:ks both lL-4 a11d IL-5 gtmc e:q:ircss:bn. as
`wdl as the active 8cerdfoti nf lL-4 within the nasal
`rnuco~:L The8c m:e by cviokine~ hi rcD:ttbting tndothc(cid:173)
`lial VCAj\!l-1 cxpn~;Si(;,n and, eon~i:sknt \vith this,
`fluticasnnc ttopiomitc has also been :s;hown to inhibit
`the :;:ca;;:onal increase in endothdia.l VCA\.:f-l c:-:prc~(cid:173)
`_;,hn (20). This action., kl!ong with a rcducti,m in lL-5, a
`cytoldne known to stimulaic the pwl.ifcraHon and
`differentiation of eosinophil prngenlt(if cells \dthi11 the
`bone marrow, can accotmt .for
`the d:1;.'trea.s:c
`in
`coi;inophils \Vithin the :nasa.l miwosa and lun1e11 \Vith
`topkal co:rtic,)steroid therapy in rhirnti:-: (20, 2 I),
`TJm; inhibitory dfrd on i11flammatory ceU uccumula•
`lion iu alkrgic rhinitis ·will also be prm:noted by Hw
`d(w,,r1rcgu!atioi1, by cortk(iskroids. of chcmokinc
`synthcsi:;; by the <.:'ipithdillm. Flutkmmne propionak'.
`has bc'.en &h(YWil to redi;tci~ i;ignifo:'.ant!y the kvd~ of l L·
`lp, l'v:IJPk1 .. RANT:ES, and GM-CSF rncowred from
`1wsal b~vage a!kr a!lcrg(:n dtatl<:'.ngc (Fi~• 4\ 07l
`indiniting l;lhiNtion ofepithdial acti\;1tion, Thi'i,a<;;-;;;;
`m,).y n:ndrrlk tht inhibiti)ry effect nf fl11tica:;.;()O('.
`prn1>ionatc~ in pr<:vcnting the seasonal ai:x:nmulatinn
`l>t' mast tells t,,ii hin the epithelium in gril.S$ polknosis
`(Fig. 5).
`
`fifgu~:~":~· 3 ~ Tnfluc-ric~:. nf pxorih)' lilCtic ilutii..::i~~•:i;,.)JK': p-'h)pi~;:111.:."ll~· oti IL ... 4
`;;;::cn::!k,;, lw ma~t cell, i:n ,caw1mi alkr,uc rhiniti~ m,,Iddiil'i!: cl al.
`f19J)-
`...
`.
`.
`-- .
`-.:
`..
`~
`
`8
`
`l-tgur,:~ 4, ;<a~ai lav;_~.gc ~-.hc:rn\.)kine lcv"Cls~ infincn,:..--:1: of fiuticasont~
`propfonate (Wddn et ;it (2'.'J),
`
`Thus,. fluticasone pMpionate n1oddies a number of
`steps in the i11ifonrmateiry paths,v~iy; it blo~ks i:.7tokine
`and c.hcmokinc generation, cndothdiaJ and ;;:pit.heHa1
`cell activation, and the tissue re,Tuitment and activation
`of mit~t cdb and eo~inophik It [';:Jlln1,vs that the fcw(:r
`thi:: number of tl:t,~s,;; prini,uy df.::ctor i:dl!'.-, tlw low(:r the
`amo.mit of inHan:unaio:ry mediators prndnc:cd and, a~; ft
`consequence, the l'e\v(:r the na~.al symptoms.
`
`Antihistamines
`i-hinilis symptnrns are media.led by
`Since many
`histamine., anti.histam.in"-,'i•Offer a.1.hera1x:utic altenu1tivc
`to corticoiiiern.ids. With short-term therapy, Hranti,
`hista.rnine& .arc n1(J.'.'it d'l'ective ,it reducing the 11curaHy
`in<'.dia.tcd sy.mph>n:rn of itch, sncc1:c, and rhinm:rhoca
`(23). 171is ca:n he attributed b) end-organ rC<::cpt<)t
`blockadt:. There is, ho\vever, a.n
`indi<::ati<m that a
`nurnb(:r or these ,1gC;;ni:', abo ha\'('. the pot,~nti;1l for
`antia1krgic activiiv that, thcorctic;1l1v, may in0rea.sc
`their spectrum {)f clinical effcctivenesi/.
`
`Studi<:~ undertakc11 in rdro sho-w that Hi ~antihisfa1ninc~
`modit} mediator re.lease Crom mast eel.ls and basophHs
`(24, 25}. The,;e in 1/estig,ninns reveal that, frir 111ost
`trnditicimil antihistamines. tht firlti;;tllcrnk activitv
`requires higJ1cr conccniratirm:; than the 11·,.-,,u1i:ihist,l~
`minic ;wtivity, For example, the pA2 vafoe, to inhibit
`anti-lgE induced nu.mt cell deg:nmulation is about 2 iog1;
`lower; i.r,, the d();s,c r,;:qu:iiwl tv abplish the a1krgic
`respunsc i;;. approximately mo-Cold higher than for
`the Hruntihistamink. activity (24). The c~;cepfom is
`oxatomid(:, which has similar ,mtialkrn:k and anti•
`hi,;Jami11(:,:;pA1 vaJi;1.;s (2()} Thus, for thcs';; c.ffects t,; lw
`rfro, rnost H, •antihistamines woUld
`foHy evident it1-
`ha\.\! to he adminbtc_red at c~;}sis -~1igher than g:enernUy
`tQkni.wd. d.vc to thc:ir ~,.xl,Htv(: dk~<:t;c;.
`
`

`

`subscqucm cosinophil accun:rulation in the alkrg<.:n
`chalk:ngc modd (.40). The inkrprd:ation nf these
`findings is afao complicated by the rcpm't that factors,
`i11ch1ding histamine, ·which irn:.:r<:.ase pla~ma prntdn
`"~_;,.:_udation, i.m::rrnsc 11:H:::diatnr r;;,cow:rv in n;1"'a.l lav,rne
`(41J, Tbus, inllibitkm of a hi:,:;tamine~rclatcd increase 'fo
`vasc\dar permeability afkr idlcrgen .:.fodlcnge, due to
`the H 1,nx:eptor bklcbde (m th<: en(klthdia! ':\Brf;we,
`codd n·.xlucc mediator rccovcrv in nasal lavmre and b.:
`interpreted as rdkcting an "a11ti-allcrgic"' cfl~cL
`irn antih:istamin(~ Hi.1t decreased knkolri{:Ht: produ,>
`tion might he expected to have ;;1 bi:oadcr dinical prdik,
`than one with al11ihistaminc activitv ~tlonc. ln clinical
`stud:i,!~, however, agrnb
`i;lhibit kukNrkn<:,
`that
`prodndion in the a!Jergi!.n challeng<'. test haw ~imilar
`dinica1 heneHh to those that do not (42, 43), raising
`some dnnbt about the intcrnrdation of the allernen~
`dutlkngc findings. Afso tnikn'r1wn i:-- \Vhdlicr or mit'the
`inhibition of miist-cd! mci.fo:)l(ir
`tdease o(:cuts
`i11
`parallel to an inhibition of cytokine release and thm;
`cdI n.x.:ruitinent. TlKTe
`is
`,xmfiicting evidrncc for
`cctidzin<:. For o:arnpk, ('.d:irizinc appears not to
`a!k~t cosinophil rccruitincnt
`in Lhc nasa.l alkrgrn
`challenge model {40) but do('.S have :such an effect in
`some other dialkng('. models, sud1 a1i skin blister (44).
`Lavage siudks
`,'l.ls(~ htn•'c prodrn::ed contrndktory
`findings (45, 46). ln our ()\Yll studies in naturally
`occurring sct1s.:mal rhinitis, i::dirizinc fa.ikd to shm.v a
`dear ;;mti-inflammatMv effect, at least HS indicated bv
`tissue txisinophil a-.xtt;mtlat11)11 (47). Cetirizim,, hm\;~
`,;\vec ha:s been found to rdw:;e nasal qJithclial I CAtvf- l
`expression in rw.hrrallv occu.rring <.]i-;;ea!',('. {48\.
`l'vlorcover, if c,~ti;izine dn1;~ pn:!i.1cnt ~osinophil
`,Kct1J11Uktti:on, grcHter c!i11icaJ benefit would be exptx:led
`with ptophylad:ic than with short-frnn use, but iliis
`docs not appear to be the CI1se. T!K d1h:t M adivc
`prophylactic therapy of H 1-antihistamines on nasal
`congestion is dso not ~igi1ifaxmt1y superiot to that of
`placebo (49), i11 co.mr;lsi to that \.vith corticosternids, A
`srndy of prophylactic fitmirnhde and bedomcthasonc hi
`patients with rngviec<l~sensi liVt'. rhinitis found that both
`pr;;vcmed the devdopnwm of 8('.-:\Somd rhinitis (50).
`
`Cornpamtiva and combirmtion clinical studies
`ln dini('.al comparirnns. corticnsternids arc sig:nifi,
`can1:ly m,'.irc effective than H t•anti.histalnim:s (51 )_ The
`in 1'itro findings with the t\vo c!asst\S of compoundi;
`suggest a c{J!Jipkn1-::.'.ntary· me.::hani.srn of action: i.,(.'..,
`th.at. there is ,l potenfod for inhibition both of :ma:st~
`cdl and basophii degranulation and of cell activation
`and co:'5inophil recrnitmcnt ff cqrticostc.roid~ and
`antihistamilws ,v~:rc used c:o;Komitinrth, thb :midit lw
`translated into additional clinical hcncfrL The limited
`swdic~ ,waflabk however, do not suppx)tt a superior
`efl<::(,.,t
`,vith h>ng--term
`regular
`thern.py
`\vill
`th(:
`
`9
`
`F(:;we 5. Epilhs:lia! .:osirmplri! ,tmi Uli.l$t-cdl m.:<:,mmfaiion in
`sea~on;iJ ,;Jforgi('. rhinitis: inilueni>.: _ of fmlphylac;fo ilutk;i~,,ne
`prt,pi;.,naw. 20() jJg 9n;_,e daily il3rnd.ding d. al. [! 'lj).
`
`For !>nrne nmrc n::ct~nt!y introdw;:ed J10i1~scdating
`antihistan1.il:ic:s, i:ncluding tcrfonadin(:, cdidzinc, a:nd
`lorat.adine, K\,-, values for inhibition of ,Hlli-12:I:> ot
`allergen:--indrn:;;;i histauiin('. :rde;:m: ure in the fo p.l\'1
`range (27, 28). ln othci: w<mb, the inJ:d bition of
`histamine rckasi::- by these .Hg;;:nts requires a cor11;cntra(cid:173)
`tion at ka:;;t WOO times higher than that those of
`fiuticasonc pwpionatc required to inhibit cytokinc or
`'"antia!ktgic'' dkcts arn
`chemokrne rckase. The
`considered w be independent of th.i::- Hi-receptor
`antagonistic activity and to be rd;i.kd. to iwusrx'.cific
`cell membram:~ stahilizMion due !:() iN1ic assoc:iat.i.on
`'<Vith t-:ell mcmhrnnes. Thi~ kads w modilkation d ion
`transport and inembnm,>aswciated enzyme activity
`(29---}l).
`ln addition, several H 1-antihfata.i11im:s have l:il'X:n
`shown to modify L>, viiro the cpithdiaJ express.ion of the
`ad]:tesion mok,.::uk lCA M -1. Both krknadi11c and
`cctiriz.inc have been found to reduce the expression of
`lCAM- l on epithelial cell lirn:;; in vitto {32),
`
`Anti.histamines mav exert their effocts either din.:.'-CHv. bv
`inhibiting end-org .. ~n effects, Qr mdinx:t!y by inhibiting
`tl:ta~t ('.dl degrnnulation. This ha:s been i11vestigatcd in
`allergen-chalkngc nwdds in ,,ivo, with nasal lavage to
`n1easure postch,ilknge mediator tt~v,.:+;. Pretreatment
`with standard do!<es of antihistamines, a!, compared to
`placebo. ha.& hee:n sho1-1m tn decrease the :r<:C.)V('.!"}' of
`mediators fo1fowing allergen challcn2:c 03t OvcrnlL
`iwwtvci, the cffe;;t;·or thc'·varkius ag;;1ts ,q;pcar to b(:
`soi.nu'.vhat v,iriabk, Thi_is, a:r.d,,istinc, cetiri,'.inc, ~md.
`kd.otifrn (34~.36) have no d'.icc:t on histamine rckase.
`although ,1 .detTcascd recovery of k~llkonkncs has been
`reported with both azdastinc and (etirizinc (34, 35).
`Convcrndy, several studie~ show decreased histmntn,~
`rdc1.u,c \.Yith loratadinc and tcr:knadmc (J7-39), but no
`cha11ge in the n.icovery of knkou:i,:nc:,, None of these
`dnJ.gs appear to lwve a
`the
`(:011si;,;t(mt d:fod (ir1
`
`

`

`Howarth
`
`cornbinat.km 1xnnpanxl with
`a.lO!W (52, 53),
`
`topk:al
`
`ixirtk:ostcroid
`
`Conclusions
`Th(: bwad d11x,t of topical corticnst(:roid therapy in
`rcdtwing the mtK:osal ai;:cumulatkm of the 1m~j<Jr
`effector cdb of the disease, mast cells and eosino•
`phils, accounts for their substantial clinical b;,:,nd1L
`The fock of additional cHnic,il bendit when anti~
`histamtncs are used ,n comhim1.tin11 'ililth c·orticnster•
`oids indica.tcs that.
`ln vi\o,
`llK: anti-inflammatory
`cW;ds on the airw;Iy of cprtk<,sten:rids (>vc:dap tb:.s.;,
`of the H_,-a:ntihiM1:1minc1s, making the a.d:inn of the
`
`lancr redundant A.n alternative explanation i:i tlwt
`the in rirrn d)h:ts of a:nt.i11i&tam.inc:;; arc not evident in
`l'ivo., possibly due to iMidt"C{IW:te pc>kncy at thc dos(:
`nst-d.
`Thus,. fo-s.t-line therapy fr,r rhinitis based on anti(cid:173)
`is a
`inflammatory a.dtYtty
`topical cortkosternid.
`si.:tc-h as fl utiea;:;one prnph-:in.att, A. bd..ter tmdcrstand(cid:173)
`ing of thos(: properties of H 1-antihistaininc nwhx:ul.rs
`that are rdevant to cell a('.tlVatk,n and accumu(cid:173)
`lation rnay allow the ,kvdopment of othn mokcuks
`with appropriate poknGy ;:1t standard wa:1 do;;;-c5,
`th: profik of anlihistarnfoes
`This wm1kl ~::,;,tend
`beynnd their in.hibition of the end-orga.n d1'¢cte'i of
`hi&taniinc.
`
`)
`
`References
`l. H,·)w.,~ll·l PH. ABC of c\llcrgk~:
`r~tl ft,,,)g.~~nfe 1-11f;t:~ ~~nfa.nts: ft r;;.iti~._tn::1-i h~i~;fa:
`forll't~mm.-:m. BMJ T9%3Hi:7:\8--76L
`lh,.-,J)N~i) P, Ft,•\:mm, UL W'1L:;m,· s.
`It\RDf~' P. Hm,::,An· ST. HoW,\IU-ll PH.
`Irnrnt.n101~ .. x~~ihsatkn1 r,.,1f t~ytokirt(~-s tH 'tilt:.
`n.:i~~--d rnlK~o.:~J of 11,}rnJ:al ;in{! _pr~r~n.n1~il
`rhinh.is ,;uf~i«~is: the mm,; i::,~u ,Vi a
`sourc,~ ,,r ll.-4, lL--5 ;m<l IL-◊ in hum,m
`;il.b·gk h1flat11rnatfon. J l1111nmwJ
`l9"93:l51:JSY~--J86!:t.
`3. HEN"[L'i A1VL J\C(>U$0N :rvm.,
`C)}M~tR,~.:r-r~·rn l\ t~t aL
`Tr1}rnunDhi❖t1)},)gy <.1f th,.:. ni1~·~\l n.1tii=>.1~a
`hi s.~-~i:-;o:nal -~i.lk~.rgk". .rhinitis.; in.:.''t'::XlS<::':.~ in
`*-'lh,st,.::cl ,~c,$ti:t<Jphii, and cpithd~i,l
`nl~l~t ~-"'.t~H~- J .A1fo~.rty ('llrt Jn.H))1~.nn:f
`l99:?.;ft9:82.1--8N.
`4. 01c1,!)A l'vL OrM'L\ H. K,\1~'-',i,rnn S.
`Siudic~ Ml n,,s,\! :,,ti"fat',, b:ui,)phih,'. cdk
`Aim . .-\Jl,,rgy )V'J\S5:69.
`3. \V,;.s,:,~,; S., L»i.: L HowM,rn PH.
`lniblmmatNy m,,di,i.ior~ in na.:.urnHy
`O('c,u-;--ing -rhini.iis. Clin Exp Alkrgy
`l99.S;:?S~22H--2;27.
`6. l\.-h:•.'lTF(>Rr S, lfotG.\:n, ST, lfo,1·:c<R:1,r
`PJ{. Lc:.H:or_y~e..,crHJoth~lh:l m.lht·s.l(Hl
`rn~>.kx~;_tfos atFd ~ht~ir t,~fo in b.ri::;nl.:.hi:ll
`~ts.thn.1~t an.d alk~,~SJ.k~ .rhinitis. -n~1r R~$.pir
`J !99:l,fi:Ficf.4. 1054.
`., T!'RM< lVf. D.-\\·'W DE. The cbem,>kine,:
`Ut~1r pu~~tniai rnk-:: in aHrrgi~
`i.nihmnmtimi.. Clin Exp A.lk:rg_y
`!996;2<•:!005 li.il':l.
`S. BA.R~-a:$.: PJ,. 'N\i.cic,1r frictor~·kappa B . .h1t
`J Hi,A,ht!m Cd! Bk,l l.'\W7:19:l\£7--870.
`9. B.',F;;J'kl.E PA. fht:m1,·)Rf' 1)_ lxB: ;)
`5rp~:-c.~i{1.t: in_hihitt)'r (>f th::.; ·~~ F-xB
`trans{~ripHon factor. Sd-:~nc-:~
`
`li). Kw.NE~ Pl .. Aix,x-iz 1l\.'L Am1-
`inlhi.1i.rnxato.ry Mtions i:,f ,tc-rnid,,:
`m~>kcttfor m~cchani;;m,. Tr,;cn;h
`Ph,,mw .. '>il Sd ! 993: l4:J36--44 ! .
`
`10
`
`n. E;,;,,,.):$il Ar, N!',\)T MS, (;.h}(;,Y DJ,
`S,u:a::s: M. Bi,:.1lQgieal acfr,:ih,,s of SN!Fi
`:ne1'(}ids tS~ed in 1~sthtrt~t. /\ftl J l{~~Bpit
`Ci-it Cir,, .l\iled 1994.;l.49:i\4
`u. L~!ilJWEl!ll LP. S!'.\li~ JD, KA~l.-\>10.'\
`AK, Swi~ \V,.Ln;>s(i DYJl,-J, Sn·n:LEI' SJ.
`Effa~ei.s. i:.if hydroer~-rti~t)ne and. S.}·.n :h.~~ti.c
`glncon;rtk,Ji<!, on lym11hocym
`it\..'=fr~··atiou "iu ~t~nJid--rcsi~t,.rnt
`:i~thmatic,. J Allmgy Cl.i\drrirn,1iid
`l' 995~95·.988.
`13. UML,"<l) SP, N.\!lRf:J.r:·,r: DK, R.>,i--V" S,
`,~t a). Th<' whibi(nry effects ,.,r ,npii .. ,a!Jy
`attivt §.lLt~.:,.:,1{_~,)rtin.•,;tds i:)n lL-•4: fL.-5 ;~nd
`inti;r.f~t~)t'f g:.:~rnrna pt(fdth..-:~il)fl by
`rnH~tred plltti,iry CD4 + T ,::dh. J
`:·\ll~tgy (Jin .frtlHYtiHt>l
`1997;.rn0·5ll·•5l9
`.14. McC(!"<XUl \V, lfow.,\H:rn PH. The
`~:.i.rv,·.:1y ~~nti ... tnn~nnn:~:.:oty .efft:l~t~• f;f
`f!atiCJ~fHlt prf,.pif~l1,,'.3 h.~. R.{.:~\: (:.'onh;tfip
`Phw:nu,,othcr 199S:9:5.:fJ .. ;_5JJ.
`!$. l-1.VJ&iN, DD, fam><:,r~ TA. S!,k.-\l'i"'
`\\''E. C.ih:cocorticotd:-1. Lnhibit cytokirw.
`rrr,).du.,~ti.nn. by hu.t:~'l.:.:l11 at~d. n1u.dn◊ rn;;"l:,:~
`cdh J AlkY!!S Cfa, famr:.im;]
`199:\95:2.98-
`! 6. h;u .. ;.,~ R. JoH"-iSO'>i ;\--f, fo,E A.
`Fii1tkH:~::i1i1e propi<>t1Hit~ ·· ·;u1 ~1pdJt-~~ on
`pH.:~dink~ll ~ind ,~lir1:i~fd c~r~:::•ti,--;n¢,~~
`R~spit i\l~rJ 1995~89 S.i.tpJ"$l A~l-.-l.R.
`17 C,\1'URo,.; LA, DHrnA.\rSR .. hmi,s:01;
`11--fK et ,,L E:,;pr,~;;sion <>f1L~4, Ccpsihm
`RNi\, and kp,ik,r, RNA, in the mlMd
`:nitt~r.-~a of pati~nts \dth St:;iist':tlitl
`rbjn.itl::: ~-fl;~t ?~f t-(~pi<i:Hl i:.~oriic.osti~roid~i.
`J Alkrgy Clin lmm,md
`199~;1/H:330-3%
`18 ~L\s1}r:,?1iA K. Tn.1. fiJ __ l-\tos.sn:'.': !\.:lR,_
`,,t ;;l. N,tsa.l i:'miM11liilb ;;nd lL-5
`rnJfr4r\ C):.pn.::-s1)1on in s.-;.:a~'-)ncd aHcJgic
`rhiiliti5! jndBCi.?Jt t1y 1)Iih.H~tl ;d.tt~1~~~n
`~)tpc:>s-ut(':: efS~x~t f:.rf .ic)pk~al
`1,.·~n:-1.kQstt:r;:)ids .. J l\.lk~rg_y CHn Inl1.nunc>{
`t998;IIJ:2·6W--frl "!
`.
`
`i!:l, I~R\(ll)l}i(i P. FE,,WJ:l< JU. \Vl!.$",~' s,
`lipu,xrn ST, lfowMml PH. Cyti.>kuw
`hn111un.fYt:.;";;Jc.~1tvhy in ~t':;).S<)t1J.f thit1his·
`:,egul~1ir~n by ~\ tr~pir:111 .t~":.1'rtiro\t('!1Y;kt
`Am J Rc~pir Ciit C.m:> t,..kd
`199 3: 151 J 90t)--l 91.f6.
`2H. -~;.-f{l~·-iTLFCi~t:r $ .. FE:tTHEk T.: \V~l.SO~ ·s.
`HMKA!d) DO .. 1-fr,W,\!('::ii PlL
`End<.>thdi.;l ku.,,,:Kytc ;;<lhcsiou
`t,toh:~cu'k~ I?~ pn~-ssi~.1:iri ·:_n ~i\~1&-.)rWJ a1h:.rgil-:
`l··:t1f-r3jii&: rdt·1/Hnt~ 10 di~e·:.:--:;S\;;"'. expre~;~.it')n
`H.nd r~-guJati-:n._l b)· t<)pi.(:ti.! U1..ttil;as..:..">O~
`pr-..~plon~c ti::-· th{~ra t"iy. l~·ur R{::$P~-r .j 199 \b
`St1ppl 11: 12},
`:n. Uni:,1 /\, Frn:n·xs W, Grnnao' T,
`Vi::.ooM T, Rm,-,Ts E. S,,foty and d"ik,,,:y
`:of (J!lt~~yt~~:r t.n:n-ttri.f:n~. ·-.;;,:jJ.h Hnt.i.el~iJtR;
`pr:.-.1pit':f)1lh": o.n di.nkal ~ign.$ ~tnd
`fni1arnntat(~ry ,::¢Us in the n~i~ai 1rnK~<):s;3
`,)f ;ilktgi(•·. p~.rtnr1hd rhin.iti.t; patfoilt~;
`.Alk:r gt)h:fg.k~ i996; l~J.4.t
`22. V'<'nM /\.J, Rm,,:E Li\-!, Ai.M-1 R., Coo1::
`C.K. Sf.:!.·i T(~. 1ntra11:a:t~i1 tluh.t:Jsonf:(cid:173)
`prr.tpionaie inhibits reco,·try of
`l:hf:·rri.c.'>kfn .. ~~s ~ind i)th;;~r i.ytc.>kinx~s Sfr .nasal
`se ... ~rt-1ion~· in aikrgi:n~l£i<l\tced rbinit~~(cid:173)
`Ann i\.lk:r2,y i\;:-;;h:tna Jn1nnn.:io!
`1996·. 77~4lfi-415.
`1-?:,. llfAi/:\R'fB Plt Clinic:if t~ffica,~y of lh ·
`nmihi,t,m1irK C!in E:,p ,-\llc:;gy l 999:?9
`Suppl J·R7 97.
`2.4. CiWRUi lV!K.. G~M)!i)C}f er. .lnhihifom
`of h!·:;t;n.nin~ rc-k:~1:s.e fr(n_11 h\tm;n). hn1g in
`d{n.> hy ,rntihi~-:tan1foe~r: ihcfr t'fi\"!ct t.11)
`i.h~ nu,: cdl .. Br J Phi;rn,;i,,,>l
`l %0;.15:39S-4<'.!4.
`1'\ "Lrt!"LE T\-fll-·i, c,~,,\Li' TB. A.zdastint
`lnh.ihi~-~ JgE .... to(:.,U~it(:d h1.ln~~n.1 h.~-~~{)phil
`bl~i<lmin.,, rnka,.~. J A11~rgy Cfo1
`!mm::.m,>l .l9€9;SJ:862--Sfi5.
`26. 0,R:"k<.'ll MK. G.R ~iJl!)CE CF.
`(};<.;:)::(}t1"ifd.~~· inh1hh1nn Jnd :-i-fin1Bl:..U!hn
`<>f hi~t.:jrnifi~ r,;:l,:::,1-~c: fi·~:::111. h:~un;1n hn1g
`J;!8iJ:1oA.7.~,--- ·~·
`,_
`'~- ~ ~ ~, ~
`.. ~, ....
`·1 ·1.•J l··.-urtK,"V' •'>$_ ;(( P~"tt:} :\ :~~frr·s. ,•\,··· 1 ··~1 ~:.;
`
`

`

`)7. Oi;._•,\'.-\,'"-~ Y, C1/Uk<:·1; ~l"K.
`c:on1p;1l:f~on.s of :he 1~j)od~1l:no.ry tJfe{:~
`of kc~fDti;\_:n.~ .. ~odiutn. cro.TI!\)giy:::ar~-:tn.
`pr<>c~ti::rol ~~n.-tl s~ilhu1;.;nJ:1\)l. in hirru.tJn
`~kin:' h11\g m1d tOn$.U fCTilSt (':(i.fl1,. 111 t. i\.tch.
`A!l.ergy lm.m;in,1! !991;97,2l6.--22.5,
`18. Kl>.rViM'R \1-;', Ci.<..,>~t-,'< R \V,
`Gi.,t.un.1;.i_.,,}; A, SH,(,U. ML Arnialk:rg.k
`t3(:tt\'ily -tif.f<>rat.~1dhie ... i-i non:-~~~ditting
`;1ntihist::rmi1h~ .. i\lkrg::/ 198:7.;41:57--t\1,
`2.9. St·t.::,.,t-~"'";. P. The rw:rnbr~ta:.> actu:,us ;._-i-f
`an.J~~t}~eti~s arid !.~·~:n-:..11sn.~-1..e.rs,
`Phanxiaco1 H.t':V 19'7:l·:24:5SJ.•··655.
`;l(}. PMo .. vr·,· PT, Pu,kq, FL, Eff,,;:; or
`c-~11n.lt)(l:.1lin inhibii_fH~ nn. hi~,t~in:.ine
`:~~~:."fi";.lion frorn tn:isi. l-.:dfa •. A.gent~
`J<\ctiwns l 9~5:.16:43 --44,
`31. tlnn;ii.<Y:s' H, T-',l.'!.><n' G, 0)}!!lfi"lr',c L
`r:t at b·i rit~•i') -inhibition of lor;1indjJ1"~
`aud d..:-.:~~cafbi:1>:y;::".~J.1t:1>:ylffra t1diut.~~ of
`hi,s;;rnim: rek::is,, fr,)m lnmi,m \-!<1!.opl:\ib
`::Hld t.:f tris.L:ln:i~ri~:- .rd,(:~1~t~ {HKl
`h1u:act~HHL~.r c;3.leiu-rn. flttx::'s :tn .r,H
`b,iwphilic: kiJ.bllcmi3 c:dh. Hiodwrn
`Ph;.mtlacol l994;47;7S9 794,
`'l:?. C,1~-nxic-1 GW, oi,1ix,m1 G.. Bu:,(.,\(3U.~
`S .. PEG. G_ f:hrn,:.\&:::<) M. Adhe,io:n
`tH<JfoG"li1es ,;Jf ailerg.j-...: iniian.1n1ati,:t11~
`rci..:tnt insi~ht~ tntq their hnic~inna~
`n,k,,. i\.!krgy !HW:49:i.~S- i 4l..
`·~·~ 1r,.n~xinv· F~{. LEj-1\•t(\ PR(;;nY J).
`KM.,l',•S<)ll'Hk, /\, Lirnru,;;rnn,· UvL
`N-.-,cumto R~•:l. Bfl~~ets n-flo:..)l";;t.~~1·dit1e a11d
`te.rfi-!t1HdtH£ . .:tn\ th'3 hHhK~~! na:S:.31 allergic.
`f ca,;.,~lit,n . ..,.\r~:b {)~,)l~it)ttbl';~·iJ J{.,~a"l ~'{eek
`S.urg .l 996:. f 22.J09-~ J 16.
`34. Srn,-,; :M-.H .. H,W.<:>(,DY l', PRrnm D,
`K.-\(nlY'·Somin;A A, Licmn,\~·;tix LJ\.:l,
`N-.-\(U~R!f) RJVI. The dfr:,~t l~t ~V:t-:htstlne
`nu th~: ;..~ady ·aJk:r gii.:: rt$p~Yr1~(:. (Jin Exp
`AHergy ·~99J~l2~2§9-<l'.J~ ..
`3,S. N.c,(:1..n•;10 R:t.·l, P&o!m D .. K.,i.<;;;;-(cid:173)
`Sqi;<.J-rK,, .A, Fkf·mHon-- L, NokM.~!' PS,
`. U.-:1nJ,)<S)"i:1?,i l. .. M.. rh,: e.ffe;:, ,.,f
`;:.-:1-:':~iilzine on t'arly aller,gk-: fi.:~:tpnnst~.
`t_,_;.;.ryngos~:<)p~ i989;99::596·:599.
`
`36. M_.,,r.-:·,:,,,1 .. AM, Pk<l1.,r, n, K.-\;_,,,,(cid:173)
`S1,rn:r:·i.:.-\ A. L!CB"\'l'~::,)1:!c,: :u,.f._ NM'J:.E!HO
`Rtl.--l. I(etl)tifonn,.Juct,:; ,!!\'.(~ting btl! 1w,
`hist~iniln~ Ti.'.'k'~i~c f.~~U•:..i~;·ing aa~;a1
`t;l1:dt~~rtg,:. \:dth an.t_i.g.;:':Jt. (:Hn Exp J\lhfr·gy
`i990;W:7!/!--:m5.
`37, D.t:tl:~~t:1::·i J :• LERf'l, n~ C~H..:'(:-.:,•\L t ~fc,to:L
`A, lVhnru. FB. A.irtialkr):!i:.: acti1,i.ty ,)f
`ll1-r~X":~pto.r ;3.ntag,c)11i:1~::~ 3$$!.tS:.,f~t~f by
`,w,al priming, .I Albrgy CHn ln-lmunol
`l 91-s9;84.492--5tl 1.
`'.\f:. AX!'>U>.iSOX M, -~,-,·)l_Jl: H. BAl.iMZ,,<IGl:,-t
`C~ .. r-.:w;,:oR:\: l}. SHpJ:irc:1s..i.ve. ,~':iT;.~et of
`l <)nttf~>J.inc· . .,,~n ~~ncxg-.::n:""ia,1~u::<:d
`his.h:tn1lnc. n.:·k~as~-: in th.i:' tlose: -"\lk:-rg.y
`199J:46:54fl--:'i46.
`39. N,\(:l.l'IH<> RM, K.,,(,!:',•·-S.011<.WK,\ A,
`LK1-n·1--:,,-rti>i LM, Fk,,n:,;:on L PRnt.:1)
`!), Te-rfen~1dine. an l·J.;..:;,;)nhhi~t.;ullt:It\
`inhibits hfaiamine rdo:;J$~ fo vfr,:, in th,'.
`fnim~n, Arn R?Y R6J)ir Di,
`l\l9l);141:l67l'il
`40 K1.;,.,-,fXT.%0~-, .H . .:l..x:r,1:11.,so);· 11,,t_ P!N-:r,;rn
`tf A!'krgtn .. J.nduced inc:nia~e ln £H)n~
`$lx:,:ific n--~~i!l te~l.~:ti~,:ity j~; bl:)i.'.'k~<l by
`~,1nt!hiStarnin;:":S i\-i.th.t.Y:.lt ~1 d.e.ar-.cilt
`r~~1a~k'H't~hlp iO ~.o~inophi~ intlr~: .. J
`Alkrgy Chu lmmuiwl 1990;86:466---672,
`4L Mnti'- !', Pn,"',o" CG. Ai<,wit;,;(," 11-L
`e\ nL Alphn 2.-mati'oglr,bulin. c1nd.
`t~os.inf}})hiL ~:.a:t-!,;~tlir prntt:iB id th<::~
`aHtTs:fr.: :iin.¾:av ·nn.H.>osa iu se;i:;:;ona1
`~~}k:rf:j,:.: .rh.in1t~s. Eut R.:?-~pJr J
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