Eficiència relativa del cross-over respecte del disseny de grups paral·lels

.. U NI V ER S IT AT PO LlTE C NI CA DE CA T ALUN YA Bi bl io te ca LLICENCIATURA EN CIENCIES I TECNIQUES ESTADíSTIQUES EFICIENCIA RELATIVA DEL "CROSS-OVER" RESPECTE DEL DISSENY DE GRUPS PARAL'LELS Autores: Marta Benet i Mora Raquel Garcia Esteban Director: Erik Cobo Valeri 1 1111 11 1'II 1 11 1 'm 11l llm lll lll l[ll ll l ll il ll 14 00431506 2.- MATERIAL I METODES 2.1.- OBTEN CIÓ DE LES DADES La recerca d'aliicles s'ha dut a tenne consultant la base de dades mediques MEDLINE, en la segona opció OVID.- Fundació Laporte; accedint des de l'adre<;a URL: Bases de dad es de la BUB: resultats de la vostl'a cerca MEDUNE rEBSCOhoSkCBUC) MEDUNE (QY!P-F uuduj6 Ltpo rU) • MFDUNEPubM.d N,UgnaIYbrwofMed.¡,ino El resuhat de la teva certa és de : 3 registres, I Bus car I Tot,): el.> reRlstr es IPreguntes més fregOents I Bibli oteca Copyright 1m, Gosurnrr Ttgud:;loc . AdapLaci6: BUB. 1m . Bases de dades de la BUB: resultats de la vostra cerca Registre complet Si us plau, sortiu correclament de le s bases de dades que con~ulteu quan finahtzeu la co nsulta Registu. nUm: 163 ImOL: IMEDLINE (OVID·Fundacib Laporte) I Materi-;;- - -r MedJcina. salut. bi o med!cin~,-" · ann - -ac -ia- .- --- --- - - --- --- - -- L ' (1 'x. ! contingut: Base de dades bibliografica pr o ~uJda pe! la National ubrary ofMedicine, Conte me les de revistts relacionats amb la . literatura biomedica, la investlgacl o 11a practica clinica AC!llalitzaci ó mensual 1966-- . ¡ com accedir-hi: S i ~lema OVIDVlEB. Feu clj~ ~ s~güent campo "URL' per entrar a c o ~~t~, Q al camp "Més infonnació' si no hi heu entrat maJ. I URL: - · -- . ~;¡www fbioseplapo rte .orrUoVldwebJhidden.c0.IT::JS&D=mesz&NEWS=n&PAGE--main ¡Notes: 1 Accés a travé~ de la Fundació Josep Laporte .. IComenlaris a: l. ~e . dbi b@ d4.bib . ~b . es IBusear ITots els registres IPreguntes mé s freguents IBi blio te ca Copyright 1m, GoSiwner TNeld$lnc . Adapt4ci6: BUB , lm . ~l!Lr--- _ ;;; ~[n::;fiiíi;;: ;'_= :; fI\<? ", ::,;'," ."-::: ¡;;",:;;.,,¡= :r.: . . ._:::i. =: · ii'iEWS;¡¡ _~;:¡ ~", ,, ¡: .,_ ;OJ . fí:. ÍfI:¡¡( ~I:: .... M ,. _ - _ . !:: ' ' .:::: ~:::: . .. . .. ~::l :'A :!: , ::i9'~?lt::~it si ¡-'D ;:;""",,= t;N"' _ . ¡: ... ¡;¡ . _= =------ ------;¡¡,~ ,", . .!t5t :7.,. ;'¡' '''''' I ¡j JilIA ~ ~ ~ g¡ J!.I ~ . ! J j~~I «: d:lA~ ~ 'tJ(.l: F 'lY ~~ d . O ",.,.,.".r :r '- ~~ : ~ ¡ . ltlO) Seguidament, es limita la cerca als miic1es que tractin d' assaigs clínics amb humans publicats entre el 2000 i 2002 en angles i amb accés a tot l'article: 2 Uvd' Se<1lch fonn .'cltCc..lpEI o VID MEDLINE <1966 to Fe bruary Week 3 2003> . ", ~ l s.__ Hll W i R. ,_w_tS __ P_I ay r ______ ____ _ U C_h _ __ _ ry~ ____ __ ____ __ __ __ r~ _ ~ iS ~ r== 1 CJ Enter Keyword or phrase: P Map Term to Subject Heading Jcro~ . ~ov~r . :@i~ Limit to: ¡;; Ovid Full Text Availa b1e J;;" Human P" English Language r Rc";ew Árb.cles: r Abstracts r EBM Review s r Late st Update Pubbcabon Yeal 1200) fl-I= El Copyright (e) 2~2(}()J Qryjd T« hno(og iO [nc Version rtl l2 0,SOOlc eID 1. 6921 .1 .83 Es selecciona el Subject Heading Cross-Over Studies es prem Continue, obtenint finalment 544 articles. o VID Mapplnc Display Combme s elections with: IOR :::J Your lenn mapped lo the followlng Subject Headlnc" Cli ck on a sub Ject he a ding to view more general and m ore sp ecmc te nns withi:n the tree Seleet Subjett Headine Explode FOt"us Scope ..... __ .. _ ---_ ... - ¡;; ,D Cross-Ov er $ tu di es r r r D ou ble-Bbnd Melhod r r : lJ¡ r ClinlcalTrials r r ~ D r Hypertension r r l) r In,uIin r r ] ) r MeiOSlS r r : j) r 'Cross!gg O ver (Geneticsr r. r O r Thyr o xme r r ' {; r H~erchol e )te ro lemia r r Ji r Blood Pressure r r .:1) r cr os so ver.mp . uarch as Kqyword ffints. • Clic k on a Subject Headine: to view its tree - re l ate d terms that are mo re general aDd more sp eci.fic. 3 ~ .. 11l B"'!9!.~ • .. __ ____ ~_ .. ~ "_ . MEDLINE o V ID <1966 lo Feb ru ary W ce k 3 20 03> 1' · ·· ··# ·· · 1s · ~ · ~[h · Hi · ;; · ~ - ry " . ....... ." . ... .... _ •.... . 1 200 1 r- ··· i ··· ···· r c;~ ' ; ' ;~o~~ ~ " s~ ' ~' ~ ~/ "' "'' ''' '' ' " ..... ... . · _ ~ ···_ --- ------- - " -- -+ = = ·I 2 ¡ hmit 1 to (ovid fuU t elCt av aila b le and h um an an d e ngli sb ¡ ,I angu age an d yr= 20 00 · 2002) , En te! Keywurd or phr a se r;; Ma p Te rm to S ub ject H eadlng 1 .: C ; b¡' ~ Limit to: r Ovid F ulJ Te'" Av ail ab le r H um an r EnsIis b Language r Review Alucles r A bstr acts r EBM Re"';e ws r La ten Update Publica ti on Ye ar ~.~ R erult s of your s ear ch: limit 1 lO (ovid full text available and human and english laneuaee and yr2000-2002) Cit a tio ns di sp laye d: 1-10 of544 Go to R ec o rd . ~, : @ C itati on .Man ag er· &!Q • ~ La inclusió deIs articles que formen part de l'estudi es realitza seguint els següent criteri: Es limita la cerca a les revistes The American Journal of Medicine (Am J Med), Annals of Internal Medicine (Ann Intern Med), British Medical Journal (BMJ), The Lancet (Lancet), The Journal of the American Medical Association (JAMA) i The New England Journal of Medicine (N Engl J Med) per ser revistes prestigioses amb elevat factor d' impacte. Variable principal ("main outcome") continua. Metode d'analisi ("Statistical analysis") basat en la teoria de la Normalitat (ttest, ANOVA, General Lineal Model...) Les pagines web de les revistes mediques citades són www.amjmed.com (Am J fed), www.annals.org (Ann Intern Med), www.bmj.com (BMJ), www .thelancet.org La ncet), www.jama.com (JAMA) i www.nejm.org (N Engl J Med). 4 6.3.- Exemple Sen n (ref. secció 2.1) Senn and Auclair 1990 (p. 1290). There are measurements of peak expiratory flow (PEF), a measure of lung function (National Asthma Education Program, 1991, pp. 6-9), made on 13 children aged 7 to 14 with moderate or severe asthma in a two-treatment two-period cross-over comparing the effect of a single inhaled dose of 200 )lg salbutamol, a well-established bronchodilator, and 12 )lg formoterol, a more recently developed bronchodilator (Faulds et al. 1991). The children were randomized to one of two sequence groups. In one group they were given adose of formoterol in the moming and observed for 8h in the clinic. They then traveled home where they or their parents took further measurements 10, 11 and 12h after treatment. On a subsequent occasion after a wash-out of at least one day they presented at the clinic again and were given a single dose of salbutamol. Measurements in the clinic followed as before and were again succeeded by measurements at home. For the second sequen ce group, the procedure was as for the first except that they received salbutamol on the first visit to the clinic and formoterol on the second visit to the clinic. [TREA T= 1 -7 salbutamol ; TREA T=2 -7 formoterol] EXAMPLE CROSSOVER: SENN,S: page 32 GROUP PERIOD PATNUM TREAT PEF BASE 1 1 1 1 310 290 1 4 310 300 1 1 6 370 250 7 1 410 390 1 1 10 1 250 250 1 1 11 380 365 1 1 14 1 330 190 2 1 2 2 370 350 2 1 3 2 310 350 2 1 5 2 380 350 2 1 9 2 290 280 2 1 12 2 260 270 2 1 13 2 90 220 2 2 270 270 1 2 4 2 260 270 1 2 6 2 300 210 1 2 7 2 390 390 1 2 10 2 210 240 1 2 11 2 350 380 1 2 14 2 365 260 2 2 2 1 385 345 2 2 3 1 400 370 2 2 5 410 360 2 2 9 320 290 2 2 12 1 340 310 2 2 13 1 220 220 Grup 1: forlsal 2: saVfor 62 t 'J 11 / 11 : 1101 (; 11111 , : VIIOI e J(; t:: E uí O. 4i > ., -' -0.2 -o Ci :::i -OA E :J :;; (f) -0.6 * .= U> ., -0.8 * O> c: "' I * .J: () -1.0 "' -o .J: c: -0.25 () ro -0.30 ,. Figure 2. Changes fr om baseline values in levels of serum lipids, lipo pro 1 eins, and apolipoproleins in al! patienu who complelcd ¡he slUdy. Top. Mean chal lges l rom ba~ehne In se lom hpld levels. BoUom. Meill"l ch.anges from basehne In I",vels of apol!poprOIE'¡n A· I. apohpoprOIC'ln B. ond Ilpopruleill(¿¡) Whill' ¡-¡¿¡e s 1nr.1,«(I{e lhe (Onllol die\: qllped bars indi cat€' ¡he w(jlnut diel HOL·( = high-densily Ilpoprolein (holeS\f~ro!; L OL-( :-. low·density lipoprOlell1 cholpqr.:rol, f( -IO lal choleSlerol, TG -lflglYtende: VLDl -( " very·loY4-densl\y hpoprOlein cholesleroL Error bars repres~111 9S% Cls lo conven Illg~)'c(,lrd~ value~ 10 rng/dl . divide by 001129, lO convert high·denslly hpoprOl ein cho leS lerol. 10w·denslIY liporrolein choleslerol. 10lal c holeslelOl. and v<'ri'·krv ... ·· del\sl\y lir loprolein cho leS ler ol villues lo fllq/CJl. rlivide by 002586 . Asler lsks IndiGne slgniflcanl dlflerences Irom baselrne by lile l""o ·tdrled [-les! .p OOO\.··p <. 0.05 cardi(j";\sc'ul,lr risk ilS~Ul'iil(ed with plasrn<-I levels of lipoprllICin(a> grca le r Ihnn Ihe Klllh pe,celllile (>0 .3 gi L) (21) . Blood enncc,"r,,' ions aoe primaoily eur>- Irolle" hy ge nelics . "nd il is gencrally belie ved Ihal dicl"'y bcror, have ~ negligihle elTcL'1. The walnlll diel mud esl l)' hui s igniflcantly reduc ed lipO ' proleill( ¡' I) le\'!d." in nlt:n (huI nOI in womcn as (l group) and in r)(tli('nl~ with hnsclillc serum level. '; greater Ihan 0 .. 1 giL. This is inleresring in view oC [he ob" ervation thin pharlllacologic doses uf 11-3 polyunsaluraleu I"nlly élcids frnm fish nils mighl have a benefici,,1 clleel on lipoprolcin(a) levels (2Ó -2X). Tlle e lrc ct uf n- ,3 latly "Litis from planl snurce.s nn lipoprotein(a) requires I"urrhcr sludy. Dielar)' fally ,"cid composition largely determines Ihe I"alty "cid composilion of se rum lipoprotei':;, which in (urn inftuences tlle rate and extent of lllr ir ",idalion (ID). Unlike salur"led and ntOnOllnsatllr,lI· ed f~lIy aeids, polyunsaluraled falty aeids are su scep - lible 10 uxid,,(ion (10). Nevenheles" enrichment of LDL pMticles wi(h pol yull sar urat ed fatly acids duro ing Ihé walnul diel did nor alter (he ir r es isra ne e 10 ox id at ive damage, ns assessed by o-toeopherol eonlenl (Ihe principal proteclion of LDL partides again,1 nxi"atiun) ami the lag lime of eonjuga led diene formalion (the unly measurc uf LDL ox idalion thal hns been ",sociated \Vith eoronary hearl di,ease in clinical sludies [29. 30]). Olher eomponenls of 544 -t I 'pril 2un{l . "l",,¡tI.., rJf JI/rcl7/{// Merlicil/{, • Vulllnlc 1 32 . Number 7 ' reduces Ihe risk [or coronary heart disea se IVas report ed (7), lwo l arge prospeclive sludies have eonfirm ed Ihe observalion (39, 40). 11 is reasonable 10 ass um e Ihal ear dio vase ular proleclion is due, al lea s( in part, 10 improvemenl of Ihe lipid profile. The propon ion o f salUraled fal in weslern diels is general/y higher Ihan Ihal in Medilerrancan diels. If the lipid profi le is improved by partial/ )' subslituling walnuts Cor typieal Medilerranean foods and oils, whieh are rieh in monounsaluraled falty acids and 10Vo' in sa luraled fal, grealer benefils might be obtain ed by partially subslituting walnuls for Ira ui· lional weSlern dielal)' fats. 17rom Hospital Clí ni c and SchooJ of Pharrnacy, Univcrsj[y of Barcd on a, Barcelona, Spaln; 3nd Loma Linda Uni .... t rsity, Loma linda, Ca lifornia. Acknow{edgmmrs: Thc au!hors lhank Nahyr Sch inca, RD. <ind An<l Pérc z,- l-Icras. RO, for di (: (ary counseling ol Ih e pMlidpallls in Ihe sl ud y. Ca lhcrinc Bouchc l, A ntonia Couinach. and Ana Ascnsio pro v idcd skillful techoical assiSlance w ilh Ih e b.borl:lwry mcasuremelllS. Granl SIl¡;pon: By lhe Cal ifornia \Valnul Commission, Fundació Pri\'ada Ca talana de NLllrició i Lipids, Fondo de ln .... esligaciónes Sanitarias de la SegllridJd Social (F[S 94/(077), and Com i Sión Lancel 199 1;338.985·92 2. Mensink RP, Kotan MB. Effect 01 cJielilly l atly dC ld~ on ~~!urn Ilpld~ alld lipoprol"im . A rnelil·an.1lym 01 27 IIlal s I\!!erl o~c l c! lhron.!) 1~92. 12.91 I 9 3. Yu S. Derr J. Elherton TO. Kris·Elhcrt on PM Pla~lna CIl( . Mslelol·pll~u,(· uve equalions cJemonstrale lh,)! SI~iH!C ,)Cid 1$ neu\lal and monounSiHur.1lrrl lalty aoos are hypochole~le!olemK Am} (\in NlIl l 1995.Gl·1 \29·39. 4. ( Iarke R, F ro\t (. (ollins R. Applí"by P, PelO R. OI(>I.1ry hplrl'i ,md bl00U chole'ilefOl: qua n¡ilall \l e fne!a'dndlysi~ of me!c\bollc ward S!Ut.ll('S BMI. 1991 JI4112 · 7. 5. Sabalé J, fraser GE. Nut<. d lIew plt) l eC live 1 00 · t.I a g, 1 1n\1 C(¡fon,try hQ . ,!t d t Seol~e (un Op irr lrnrdo!. 19 9" :5 11·6 6. Exler J, Weihrauch )L P(Qvl~ronal table on I/'Ie <.o nl cflt ,,1 uI II \''la·] t.llly acids dnd olh('f fal <ompont-n t~ In \e l eCle tl j Oo.)d~ Wash'<l9\ QO . OC' IJ ') De pan ment 01 Agltcull ul e. 1 986 (nub l'caIIOil HNIS/Pl· 1 0J) 7. fra~er GE. Sabat~ J, Bec~on WL, St,ahan TM . 1\ poss ;b 1e pl ole Clwp efff' C1 01 nul consunlp¡ion on ' ISI:. 01 coronar y h ea n d l ~ea~ rhe Adv<'''''SI l'I~ ,l llh Sludy Arch Inlern Med. 1991. I S2 .14 16· 2'1 8. 5abalé J. Fraser GE, Burke K. KnUlSen Sf. Bennert t-I. Undsted KO. Efferu 01 walnu\s on serum lipid lev~l~ arld blOOd !1res~ u ' e In nOlrllill nl~n N Engl } Med. 1993.328:603· 7. 9. Steinber9 O. Parthasarathy S. (arew TE, Kl'loo le. Witzlum ll. 8tci'0nd (hole~lelOl l..-lodlfl(aliollS 01 10 ..... ··cJellslly [¡ PO!1tOleIO Ih,)\ In(led~i' ,1~ .11r.elo, gcnlCi\y N Engl } Med. 1989.3209\5 ·24.. 10. Tsimikas S, Reaven PO. nle role 01 dlelary lilUy a(;d~ 111 hPOPf0Ii'Hl oXlua \10(\ and ,)\h(!fOscleroSlS (wr Qpin Llpldol 1 998.930 1·7 11. Zambon O, Ros E, Casals E. Sanllehy C. B ertome u A. Campero l. Ef1er:t of apolipoproteln E polymorphism on lile ~elum hpld re~polls.c lü d hy¡Jol,p" demi( óie! ri<..h in monounsallH"!ed lally a<..,u s ,n pa lll.' rm wllh h)'pe((h()Io,~ terolemla and (ombined Ilypell,plden1l~ Am ) ( 111 ' Nlllr 19Y5.61 1,ll·a 12. Kri5·Ethcrton PM, Dieu{hy 1. Oeslgn (lI!erli! lor ~\IIdiE'~ e ~ ,1rnin l nfJ ,(\rll'lIl.1· ual f.3Hy ació eneas 00 (a(d l ova~cular d ls e<r5e m I- . f ao.: lu rs human dnrl dn'{(Ial s'udle~ . Am 1 Chn Null. 1997,65(')uppt): I 5905·65 n . BUlZard ,. 24·hoUf dieta ry (ec ,\1I a.,d f()od re(OItI mel1 1O d$ In. W,lIetl W ed NUlflhonal EP ld~," ro l ogy 1d ed Nt-w Y Of \:: ' Q"lold Un .... PI . 1998 '>0·7) 14 Vál quez M. Alegrel M , Adzet T. M erlos M . lagun,) le. G~ml l hfOl" medilies aeyl com pm ,hon 01 l we r nllcrosomal pho~ph ol i p,d) 110m QUII 1 C<l 'pl g!oo \(\/ l thoul promoling perox iwmal prolrlel<rt !Q1) B.()(hem Ph.1lmacol 19 93:46 1515·8. 15. Kleinveld HA, Hak·Lemmers Hl. St3l anhoef Af, Dí"lItuker PN Apolipoprotein Apolipoprotein Lipoprotein(a) 0.05 A-I B :;: ~ o .= ui ~ a:i' ~ -0.05 o..c OJ 0 '- -J a.~--0.10 :=o.e. O ~ c: a. 0..- <t 8.~-0.15 c:'= e .- o a. ~ ~ 8. -0.20 O> .- c: -' l/un onu , , T '7777)1 ** * walnulS Illal h av!;! anLioxidalll pOlelllial, slIch as a-IOcophcrol and o lher phytochemicals, may be responsible for lhe la ek of ehange in LDL oxidizabili¡y. Nonetheless, Ihe fael Ihal walnut intake is assoeiated with a redueed risk for coronal)' heart disea se (7) argues againsl a n atherogenic effect caused by allered su sceplibi liry of lipoproleins lO oxidalive damage . Besides impro v ing the se rum lipid profile, wa lnul consumplion mal' olfer additional cardiovaseular proleelioll. Among nalUJally oceurring foods, \YalnulS are one o f lh e highesl sourees of the n-3 faH y aeid o·linolenie aeid; lhey contain approximalely 7 g of a·linoleni e aeid per lOO g of edible matler (6). In recenl repons fr om large prospeclive studies, dietary inlake of cr-linolenic aeid has been inversel)' associaled \Vilh risk for falOl coronary heart dis ease (31-33). In a seeondary prevention trial, a Medil er - raoean diel enric lled with a-linolenic acid had a slriking benefieial effecl on coronary hean disease morbidity and mortali!)' when compared wilh a prudent western - type diet (34, 35). The low ratio oC linoleic acid to a-linolenic acid in tltal slUdy (4.5:1) was similar 10 Ih ar seen during Ihe walnut diel in our stud)' (5:1). Dieta,)' o-linolenie acioJ mal' reduce lhe risk for dealh from corona,)' h ca rt disease because o[ ils anliarrhylhmic properlies (36) and ol her antialh erogenic effeets (37, 38). . Our inve stiga lion adds furrher weight 10 Ihe ae· : cumulaling evidenee Ihat regular intake (1f nulS h as a cholesterol-Iowering e[ecl (5). Since tite firsl ep- :. idemi o logic ev iden ce Ihal freguenl nul consulllplion 1I11¡;rmillrSlcrral de. Ci¡;w.:ia y T<:l:lIl1Iogl¡¡ (("J( · Yf. S/\F 117 /021:'). and OU 96/2132). Req/¡eSfS for Sil/gle ReprillfS" Emilio Ros. MP. Urrd Cl ini c NII' ¡rili on & Dietelics St:.rvicc. Hospital Clinir..: r rro\'ill c i~lI. Villarrllcl 170, E-08036 Baredona, Spain. Rl'qU(!SfS ro Prlrdwse Blllk Rcpril1(s {mil/ll/lulII, }(JO I'Ppic:sJ Bar · b,.rcr t1ulbon, Reprinls COllrJirlalur: phunc. 215·J51 · 2{l.-i7: t:·lluil. [email protected](1nlinc.org. Cllm:nf AllflJor Adclre.ues: 01'5. Z~lInhj\11 allJ Rus ;mJ M s. Camp· eN: Lipid Clínic, Nulrilioll & l)i¡;IClil.:!\ S¡;rvit.:c. Hú s pilal CHnie i Pro vi ncial . V illarme! 170. E ·O¡:'¡O )b O;rrCdOll:I, Sp; lill . Dr. Saba t ¿: Dcpanmcnl of Nutrilioll. $¡:; h úl,l l "f Pu hli ¡:; J·h;;¡lIh . Loma Lindil Univasit)'. Lum a Lmda , CA. 9235 11 . Drs. Muño1.. Merlos, <.1 mi lélgun~ : Ph"rm~rcolngy Uni!. Sdlt)~) t I) f Ph;:lIm~.cy. Univcrsity of 8arr..:clon;t.' E·OS 028 Uan.:dOl1il. Sp:1 in. Dr. Cas,rls: Oeparlmel11 of Clínical lli ochcmis lry, Hn sp ll ;11 Clmil.' ¡Provin cial. Villarrud 170, E·!JMO:l6 U(ln ; C10IlH , Sp<1 in . /lutllor Conrrib,1flO/¡S: COllc¡;plion "nJ Jcsig.l1 : O. Z' llllbóll. J. SJ b~I¿. E. Ros. An .. rly s is alld inlerprelalioll of lhe dU¡~l: D. Z<tntbó n. J. Sa!la!e, J .e. L:lguna. E. Ros. Dr ... fting of (he anicle.: D. Zalllbón. J.e I.;¡guna. E. Ru .... Criliea l n;visi~m nf Ihe anicle lur imr ul'lant ;Iltdlcclu:tl ('1)11 t ~n l: O. Z <..tmbón, J. S~lbnte, J.c. L¡¡guna . E. Rtl~ . Final appro\'all.lf lile :inicie: D. Zi llllh ún, L S"batt:, S. f\lurlo/, l:3. c' lInp cro, E. C~I<;<lIs. M. Mcllll:-' , J .e. l..;.t~t)f)d. E. ¡{!!s. Provisiun uf stfl(Jy ma\cri<lls Ilr p:l!il:t1t.':>: O ?aJllhón. !J. Campcrtl St"listil:al e:<p!;rtisc: D. Z~.mhl · iIl. J Sab;¡tC. Oh l <li lllng u f fundill g. D . 'Z~n\bú rt . J. S:ilh ~ IIi-. J.e I.:tgu na . E. Ro:.. Admmistrotrvc. I cc hniGll, (lf Ingis lil: ~uprort : S. Mttút'f'., E C;t :'\ <JIs. Collcc.:llnn ~mJ a~selllhly nI tI ... t;,: s: Muntlf'. H. e .IHlp erl). E. Casal:-., M. Merln~. References 1. Ulbrich[ Tl, Southgale DA (orollal)' hean ulsea ~e }ev~n t.lrltld¡y liJ(lor~ Rgure 2: R ec tal blop sy speclmen from a patlent wlth acu te radlatlon proctltl s rtlree crypls show necfollc CpiUll?lIvm i1nd in\lasion by neulroohlls an d eOSlnophtls wi lh fOrrnatioll 01 cry O! ab ~ cessl;'s. Foca! mucln de ol eti on of crypl epilh el ilJm é lr1d damage in the superficia l epilheUum are .,Iso vi~ible. Chronic inrlsOllllalory "l'il~fale In Ihe l amina prop'¡a 15 negtiglble . Figu(e 3 : ncct .. r blopsy speclmen fro m s<'l m e patlent as n gu fe 2 afte r tr ea tment Arler a cycle 01 topie.)1{l \liyrale . at)l)c8canc:e 01 mUCOSl\ has relu ln ed lo norrnal. ocdcma, e:rvth cma, and erosiOflS. Bu rvr< u e lcd lO improve ment or rcrnís sio n il1 a ll b\,lt ( mc pati r nt , whcreas on ly f our patient~ on pl ("\cc bo improved , and one worscned . Superfic ial cpithclia l damag e :1nd inOammation werc neg li gib lc bef ore tre~tJn e Ol in h <.ll h $ wd y group s. J\g("\i n. impr o vemenl was obscrved in m o~t palie nt s aftc r but )' r ("\te, bu t o1J ly in Ihr ec patiL' n t~ élfter salíne ( li gures 2 ,nd 3) . Co mpl i: m ce wa~ gooJ bec<1\,1se no pa.rticipant r cntrncd more lhall t \Yo llnllsed cnellHI~ at lht:: end of tr e:Hmen t. A~se~sment of thc d ata sho\\'cd that lhc advanta ge of b Ul yrate (wcr placebo alld the c<lrryov er C(Tect wcre so ma rked that the od ds rat; 0, in ~O Il1C instan ccs, could nOl be qua n tifled, illas much :!os lhe od ds rati o approachcd inftnit e valu cs. An anal ysis \Vas thu s performed co m pari ng o nl y dél ta from lhe first 3 \\'ceks of tr ea lm cnt. Thc adva nra ge of but r rate ove r pla cebo , expressed as 95"/" C I, odds ratio , anó p valLle for clinical cndoscopic an d his to l ogica l findin gs is reponed in the tabl e. Discussion Earl y radiatioll-i nd uced sy mpwms are frequent in patients sub mi tte:d te radiario n therap y f ox: ca n cers in (he pelvic reg ion and h :1VC a furthe r ncga tive e lT ecl on the qua li ty of Jife in these p atients. No pr ovc n effectivc therapy is, al prcse llt, aVí\il("\bl e. Th is double-b lind pl¡:¡ccbo·con (r o ll ed, cr ossove r (rial in tlicatcs that t op ical bu ry r atc at adose of 80 rnmol/L (80 mUday) is eff ect iv e in A RP. Relap se of syT n ptOms was observed in lhree paticnts after wil hdr awal of tteatmen{, sugges ting that the op (imum coursc of butyrate is lon ger ihan 3 wee ks. PrcUcotmcnt c nd oscop ic a nd hi sto l og i ca l ab n on ll aliti es wc re oot distrib ut cd homogencou sl y, a nd \Ve re, in m ost ins tances, min or. Desp il e the p05sibi li t )' of s amplin g e rr ors, th e l eve l of s igniflcance , after butyrate the rapy, was reac h ed for e nd oscopy an d appro("\ched ir f or híSlo l ogica l rindings. ARP sy mptoms , occu rr i ng dur ing or soo n after treatmcnt, spon tan eous ly re so lve, in 1110St inst("\n ces, wí thin \I, 'ceks or a fe'" mo ntb s. The risk of de velo ping chro nic proclit is besides d epe nding upon the to[a l rad i al í on dose, is grcatly increased br conco mitant patho l ogical co n ditíons , SUcll as d i abetes and vascu lar dam~lgc} or old age a nd tJ1 C occ urrenc e of ea rl y radiali on toxicity.'· · O f lhe se v~rious fa c tor s, o nly ARP ís pote.ntially pr e"cnuble, but pre lim in ary findin gs we re th at p ut ative drug s, such élS 5aminosa l icrlic acid, epidc rmal grow(h factor , a nd pro s taglandin s \Vere nOl full y satis f actory. r~1I The prese nt study pr ovide.s strong bUI preliminary evi dcncc that sodium buty rat e ís effectivc in the lr eatmc nt of ARP. Whether .ea rl y admíni stra it on o f this SCFA also has an c[fcct on lat e int est inal r 'a diation damage remain s to be established. Fina ll y, ARI' repr ese nts a uniqlle hum an model in w hi ch a n ox ious agent is app li ed, for a sho n tim e, on a pr evíous ly n orma l mu cosa . Thc effic acy of sodiu m butyr:ttc in enhancing rhe h ea l ing of mu cos al Icsíons and rcdu cing relal ed symptoms furrncr supPOrtS the rolc of this agenr in rhe trealmel1t of ulccrativc co li tis and ot h cr mu cosa l di seases of lhe co l on.I~. I. Contriburors AI I inve"aig;!'I Or!' 100k p¡1rt in !.he p l:ll nning.o f lh e de~'81 1 of the 'óllldy :md \\"ere involv ed in wril ing ~rld re\ ' i ~ i np: l.he: p::rpc::r r V e mi~ I.:o fl ce i ve d lhc slUdy :.nd w:.~ tlle principal IriRI inl·C5IigllIOr. V C~~ ~k , p L Fr:\o !'~ o , " !'tigli:tno w ere re~p() n ~ ib t e fo, Tc en,iunelll , f o ll ow~ up. :md cn do~ co p y u( pntic" l ~. r rino"", WR~ ,c5pon~il-1c for lhc re cruilmen Cof p:u .. iem, "lid rstdiolhe,,~p y . A March c J!EiRnO W;lS resron!iible f (\T hi:"o lc ltic<I' d...... G Vi tl Qn i bl indly co lleel ed ;lnd cI .. bor.lled dRU ob t;tined (ro nt mllhiplc $o urCC!i . V O:lgn: lrdi w:u fc spnnsi blc for S lwti s ,i C;l 1d.,u,. R C:lpril1i co n tribut ed by conceiving ,he profocn l llnd coor din;lting I n;l" y IIspec(!' o( lhe Mu dy. Aeforenc es 1 Zilnrnerm;ln n r-o , f ekl mann 1-11. Rndi:l.lion procliti!i, C1inic .. 1 :md pl'llholog'lcal m:m ifcs,:.,io ns, thrr:\py ~ n d prcrh)'lalfis of ::' CUl e 3nd ¡:.te ¡njuri o u~ efTC" cts o( r:.di:tllon on lhe rcct:tl rnuco~:t . Srra}r/ eflll lt ;r O"ko l ' 998; 174: 85-89. 2 Nu ssbAum ML. CRp:lnRTJ, \1;Jce~e JL . Radinion-induced ¡n les ,in,,1 Ini ury. C ti ,. PlaH SlIrg 1 993; 20: 57) -80. ) l3abb RR. R:tdi::'lion rrocticis : 1 rev;cw. Am ] Gaj( roc"Uro /1996 : 91: 1309-1 1. 4 Mitlcr AR, Manen so n JA, Ndso n H, el al. Th c in cidence :.nd clin i<;,, ¡ con'icquellces o( tre ;l( ment -rcl : lled bowcl injury '>'Ir] RQdiar OnC(l1 Di "l "" YJ 1999; 43 : 8 1725. 5 KClchh¡u R, Srir ::\m PV, Sh:.,m<'l SC, Goe l RC, P:ttel F. N::\ntr:t l hislof)' of l"Ie r:.di:'lion P1octo5igmoidi\is IreAl ed wir.h to pic::. 15u cr <'ll p hal e susrensio n . D'g Du Sá 1 999; 44: 973 -78. 6 Casa le V, Fracuso P, G rani A, t..'ren1a R, Slig li~n o V Suc r<'llf:lle vcrsU! hydrocort iHme enC1T1:'S in lhe Irc:Hrnenl of fadi;¡tio n-, ndu ced pr oc liti!. 1101 J Gamon-rr r:rol 1993¡ 25: 4 1. 7 Dubt:lY BM, -f1¡RnleS HD . Ch ronic radi:tUon d3mage in thc fl'lt recn .. !m : <'In IIn.l l y~ is of Ih e fraction:nion, lime and \'olurne. Ra dio rlt ,,. 0"'0 /19 94; 33: 41 -4 7. 8 W<'Ing ej. Lc::ung S\V, Che n HC, el ,,1. Thc co nc1:nion of :lCUIC. to.!tiei()' and latc tec':l1 ¡ "jU f)' in radi Olhcn py for c cr vic ",1 cncin c ma : c\"¡dcncc li u~ gcSl¡\'C: of co nscque.nrinl ¡;nc dfe ct (CQLE) . 1... ] R ad ,ar 8i ol Ph ys 199B; 40: 85-9 1. 1.1 Scrm S C r f1~~ .. tJvcr 11, .. I ~ in drnrC<l1 rc :. c:or ch. N ... w y", .. .. t,·hn \x ,I,'\" and f"cr!"lT X III in cx perimental «(llltiS in Ihe 1" 31: crrccts on "ól nd Son~, 1993. tran~g¡ut~min;1se :Jc li \'ity. GaJlrot:lllt r otn¡::y 1994; 106: 399 .......,04 . 'l U'l\rgc::nio G, COSCII1. :\ \1, ~ulrenll lH 1, CI al. UUlyr ;u..:. mc~", lamin ..;, 15 Oaughan e/\, C .. nn c)' r A, Buch:rn::rn RO, el ..,1. :\ r : , nJ , IIlIl ~ .. : t1 In:,1 1" 10 Mtlrtemen FV , Ni c¡ ~en H, Mulvan r MJ. el:tl. Sh nfl chai n btty :\~!iC~'" lhe effic3ey of S_ASA f or Ihe pn :: \'c mi vn "f r ~ I J ,:r(l. ,n · : nl c l iu~. 3cids dibl e i so ):llcd human co lo nic re$l st3nc e 3neri es. Gur 1 990 ; ~I: Gli" Ollt:ol I QQ3 ; 5: 1924. 139 194 . 16 M cK elln3 KJ, l...i¡;~1O S. K ~ u(fm"n GC. el al. E"" llernr!lt 11 Kvielys rR, Guoger ON . EtTect of vo l1'l\l k f:m y Reíd .. 00 blood no\V grnw lh fa et ..r c::nh:rn c e~ ,"telilinal Olrlnlic :l CI ""I \" :"Ind UN :\ and o X) 'gen upt3kc. by (he dog co lon . (jaJ'I"(I('II/(r(,I"K)' 1 98 1: RO: COIIHent Jft cr ;\cute ; , b~ lnm;n:lt r;Jdi:"llll 'n. SII'J:0Y 1'1 0· 1: II ~: 962-69. (,26 - )2. 17 Ddancy JP. nOll.,:rC r\ . \t ~ . r c1cnlivclu~ 1. "~i~"f'n'~IPII!1 11 11" 11\1> ".1 11' ,1 12 $akal 3 T Effecl5 of shC"l n -ch ,d n (:. tlY ~cids ('I n cpilhcli:J1 C( I! .~ IUnlcn [H 'nc<.:t' :\p'I,i lr ~1 (;\di;Jli"I\ in;ll ry o( Ihe: 111\1~'"'' ,,1 11,, ' ,,11 di prolifcr;¡li"n and muC\J5 rc1e a.~e in lhe inle~line I n: Rm:hc AF, ..:d ShQ n-chJin fally 1I ( ld ~: m e tab('l li ~m a nd clinic :J 1 imr u nan c ..: Repon hnIVCI. /?<I" rur n" ¡flf) .I : 1~7: 010'10'). of the !O\h Ro !~ Confe r ..: ncc ('In M edie::! 1 Rescuch . Co lumbll~, Ohio: IR Vcrnl:l 1' . r\,'.lrdl~ · I '.I.(\ . ,"1) A. (':ll'fI11i I{. Fncrl (;. C:,'Tf:'" (; : 1 d. Ros~ L:lbo rJtmic s, 19°1 : 61 - 67. S ,,>ln-~haill ClIlV ;ll· id 1,I[,i..:,,1 Irt:., l lnnll i" di'l.ll " l •.• " IIr \ ···· "hit. 13 al·Sabbagh R, Sini crope FA, Sellin JH. Shc.n Y, R-:-ube in L. Aliuro" !'lra" "'u,,' (h.-. ¡ 90'); 9: ~II'} 1 \. (\ ':JIUJ\inn uf ,hort -ch:tin f:HI)" :tcid cnem:l S: tr el) lf nCJl! of radi atinn 19 Ki m Yl. S il '.,·' . ...:h~ r "l I :t UY:túd" 111 ut .. :.:r:lr, v<: c·, h ,O' .,:" ,. " .• ... l ')')\(. prtlcliti5. Am J GaJ{Tf,,·ul.;rt'/ 1 9Q6; 9 1: 18 14 · 16 . ;( ,: 117., 1. I Clinical picture I Eosinophilic pustular folliculitis SeaN Dale. J ames Sha lV A 29-yea r-old Hr V· negative man prese n ted with a Iyear his[ory of a widesp rcad pruritic e rup lion . U n succcs .. rul pt;or treatmems had i llcludcd is ot rctin oi n ~ Ollocinonide gel, indometh<Jcin: crythromycin, dicl oxac illin, ll UCf) l Hl 7" lc .. loratidiuc 1 ce ti rizine r doxcpin ) and ullravioJcr 8 ph oto lh erapy. Ph ysical ex<t mill ation rev ca l ed clu S lcr s of ery lh t: Jll rJl( )(t ~ follicular papules and pusrulcs primarily on the h ead, n ec k, and uppcr body ( fi g ur e A) . A bi opsy spcc im cn sho\\,Ied J. mi xt: u dermal perifollieular infiltrare of Iyrnpho<.:yte:s, eos in op hils, and histi ocY 1 CS w ilh necros is of ff)lIieular epl Lh eliulll conflr ming the diagn osis of esoin op hilic puswlar folliculitis (Ofu ji's di seas e) . Aftcr u nsueee~sfu l lri:lls wilh ísocretinoin) antib io ti cs , ciclospo rín ) and da psone , 0·1% racr ol imus oin une nr (tap i ca l FK·506) a pplied ("\Vi ce daily rt::<;ultt:d in near comp l ete r eso lution of l es iom; a nd pn l nrus in lO days (figure B). During an inadv e rtant 5·day penod \" ' irJlOLlt u ca tm e nt , a ll lesions r ecu rr ed, but resol ved rapidly u po n r esu mpti on of lreaunenr. Tac rol imu s oi ntm e nt , by inhibi li ng inte r1e uk..i n -2 forrnali on and T -cell acUva r.í o n, is a por cnt imm un os uppres sa nt with potential for topieal lIS~ in Of u ji'<; disease. Sectlon o' De rm ato l ogy, Unlverslty o, Chlc¡:¡go Hospital!!!. Chlcago . IL 60637 r USA (S Dale M D. J ShZlW Mol 1 231 T HE u\NCET • Vol )56 . October 7, 2000 1235 THE LANCéT· Vol 356' OClflber 7, 2000 1 .o ...................................................................... .m .................................. ...... ---------------------- -- ------ - I -; ~ ¡j '" I IEi;:¡y;epo ty] Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study (ÁG5) [421] Marrin H Brulsche. Ingrid Carien Brutsche, Mohamed Mu navvar, Slephen ) Langley, Ca l/1e rine M Masterson, Peler T Da l ey - Ya les, Ronan Brown, Adnan Custovic. Ashley Woodcock Summary B ackgrou nd lnhaled cortlcosleroids are currently lhe cornerstone of asthma treatmenl. Some studies of high·dose rluti casone propiona\e in patients with no or rm ld asthma have , however, suggested substantia l systemic absorp tion. We inv es ti gated the pharmacokineticS of fltJticasone propio na te ;n pa tients with asthma receiving app r opriate doses (or severity. M et hods We did a double-bllnd, r andom i se d, CfOssover study in 11 patients with a st hma and - 13 ma\ ched h eallhy control s (age 20-65 years: as thm a patientsTorced expiratory volume in 1 s < 75% and stab le on high· dose inh ale d co rti cost eroids), Patients r eceived one 1 000 Il.g in lra veno us dose or 1000 ~g da i lv for 7 days inh ale d (via s pacer dev ic e) fluticasone propionate. In the 12 h after dos in g. wP. monitored plasma fluticason e proPlonate and cort iso l co ncenlrations by m ass . ~ - p · ic · t~o01 et ry and -· compet itive - i,nlñ~ñoassay Yfi\h liSe"Oi di.!:.e~ . t chemilumln escence , Anafysis was - by ·,·ñ tention lo treat . Findings Atter Inhalatioll. geomet ri c mea n values were signiricantly lower m ttle ast h ma group than in contr ols for fluti caso ne propionate plas ma area un der curve (1 082 (95 % el 850--14511 vS 2815 pg mL ' h ' 12262-39 49 1. -62% differen ce 14 5-721; p< O-OOl). maximum concentrations {lU 1 91 - 159\ vs 383 pgJmL 13 02-5461. -68% (- 50 to -8 1\; p<O·OOl). and systemic bioavailability (10-1 \7 .9-14·0 \ vS 21·4% 115-4 -32 .2\. -54% 1 -27 to -701: p=O·OOl). In traveno us..cJose cle arance, vo lu me of distribution at steady state. plasma hall· li fe. and mean res idence time. were similar In li le t wo grolJps. L ess suppresslo n al plasma cortisol concen lr a li onS was seen in the ast h ma gr oup than in control s .::1 - 12 h afte r inhaled nuti caso ne propionate. Interpr etation Syste mic availabi\lty of fluticasone pr opionate is substantiaUy \ ess in patie n ts with modera te to seve re asthma (han in healt hy controls . I nhaled corticos tero id s that are abso rb ed thr ough the l ungs n eed to be assessed in patient s who are receiving doses ap pr opriate for di sea se sever it y. and not In normal volunt eers. L ance12000; 356 :556 -6 1 See Co mm entary page 527 North West lung Centr e. Wyt.hen shawe Ho spltol. Ma"chester M23 9l T. UK (M H 8rutsche MO. I Carien 8rutsche PhD. M Munawar MO . S J Langley Ma . C M Maste(SOn R(; t~. A Cust ov ic MO, Pro( A Woadcock MO); Glaxo Well co me R&D, Stockley Par\( West, Uxbrldge. Mlddle sex, UK (R 8rown PI,o); and CUnleal Pharmacology, G I ~xo Wollcome R&D, G,eenford. UK (P T Dalev·Ya tes p"o) COlfospo nd once to: Pro' As l llCy Woodcock {l· lunll : tlshle y@ nw1ung.u· net . colnl Introduction I Sin cc the ir in troduction a lm ost 30 years agO IMak 'd corticos t eroids have pl ayed a cen tr al pa rt in me Ir eallllem of aslhma. Thc:se drug s halle alm ost enti re ly r c:p laccd mainlcoance ora l co r ticoste r oids, wbich had ma jar adverse effccts. lnh al ed co rticosler oids, becausc of tupical applicati on, hav e a s ub stan tia ll y beHe r lherapeut ic indcx than oral s[C~ro id s.l.I F urth cr im proveme nts ha\'c bccn seen beca u se of rcduced oral bioavai l abi li ey fOf nc"·;er lnhaled co ri cos t ero i ds. About 20 % of me tO lal inhalcd dose from mo st m ctered~dose ¡nhaters is depositcd in the lun g5 and 80% stays in lhe oroph:uynx and is swaJlov.'cd.' Mol cc ulc s wi[h a high h epatic first-pass m ctabulis m and l ow ora l bi oava il abi li cy, such as Outicasone propionatc, lhcreforc, havc l owe r systemic exposure than otht:r in ha\ed co rticost eroids.4 " For flu ticasone propionatl!, any syste mic :Jctivity resul ts fTom absorptio n of the drug d epos i ted in the lun gs and its oral biuéwailabili ty is negHgibl e. F" luticC\sooe pr op ionatc has a high mcrapc utic i ndo : and eOl c3 c y . l , ~ The drug has beeo used su ccessfu ll y ror several ycars fO I" a \1 s everities of asthrna and has pr oved lO be \Vel! wlcrated. No clinically il11portanr systemjc effccls a re rep oned for l he no rm al lhe rapeut ic dose rangc .; •. , By co ntra sl, pha rm aco kin etic swdies hav e suggestcd h ypothala m ic-p itl.li tu y-a drc n:t1 s uppre ssl on with 11I gher d os es. Howe:vcr, th os e s tudi es ¡nvolved normlll vo lum ecrss, ll \' or pat1cm S \V ho had mil d asthma and \V cre r ccc iving i napproprlately high do ses, well in e:<.cCSS of lho se nc e ded to eo nLf o\ their di scase .H . .. . ~ In pal i cn t$ \\.Ii th mod e rate or scvere asthma requiring higher dose s of inh alcd corricoste ro ids, factors s uch as airtlow o bstru ction and ven til ation-perfusion mi sma lch cou ld alter drug dcpo s ition in me lung and ch ange syste:mic absorption , To c1ari fy lhe sa fery of highcr doses of Ouricaso ne propionatc in asthrna, \- .... e stu di ed lhc pham lacoki netiC1 an d pharmac ody nam ics of lhe drug in patie nt s with m odcratc ly sevcrc asmma co mpared wi th no nTI al con tro l, in a randomi se d doubleblind , doubl edumIOY, crosSO ver design ( fi gure 1). Methods Study populalion We rec ruited in divid ual s fTom outpatic nt c1 inics at the North West Lung Cenue , \Vho had ph ysicia n~di agnos ed asütma, gave wotten informed co n se nt, and were ag ed berween 20 years and 65 )'ears. The inc1usion criterí' included foreed ex pi ratory vo lum e in 1 s (l--"EV.) low er than 75% at sc re ening , prev i ous bron chodilacor use, an d I s table co nditi oo on hi gh -d ose inha led conicos tero ids ; (beclomethasone dipropionate [Bor] 2000 ",g/day al budesonide l 600 ",g/doy). For eaeh pa ti enl, \Ve sdect e<! THE l.AJ'\lCET· Vo l 356 · Augu~ 1 11 , vol unll.:l.:fS ( g~nl.:rall y s t<lff and n.: bmve'S of s tatf at West Lung Cent r e), ma te hed f or sex, age, a nd indexo A lJ participants were non-s m okers (3=06 Exdusion crilería were: c1inically impo rta nt disease othe r than as thma , Or both, pr egnancy or l acta ti on in wom en , suspccte d . hypersensitivity to inhaled corricosteroids, [r eat ment with or31 or parenteral corricos t ero ids in me past 6 weeks, or inhaled nuticason e propionate in me past 2 m onms. p .. u,..icipants were trai ned in an op ti mum inha1ation . technique befare e nrering a I-w eek run -in period o Th ey r andom l yass i gned 10 00 ~ g fluticasone pr opio n ate f.1g [Wice dai l yL or a t he r apeutica ll y e qu ivalent d ose of2000 ",g of BOr daily (1000 ",g twice da ily ), inhaled at 0800 h and 2000 h from melered-dose inhalers wi th use s pacer devices (Vo lum alic, Gl axo \V'ellcome, UK; l). asscssed adhere n ce by wei ghing the ae r oso l ~ " "'.Ani s ters before and afte r each uealm e nt periodo On the befo re me pha rm acoki ne tic sar np li ng, pa rt ic ipan ts teleph one d al 2000 h te r em ind mem ro rake the l ast ~ t the pre cise time. We asked partic ip ants to S lr e nu ous exercise. The next day all ended the study-day visi r ar 0700 h after ig ht a nd abs ta inmg fr om alco hol fur 24 h. \Y/e baseline sp iromer.cy and bl ood pressure, FEV, run·in 1 On study day 1, 6 received Inhaled intraven ous Outicasone ftuticasone proPlOna\e propjona te palienl wilh extravasaUon of intravenous dose (dala n ol in an alysi s). Char.1ctcrlsllts Con lrol lln=1.3) A $l hn • .l group (n= ll J Dem o grll p hy Age (years) 42 (12) 45 (t0) se~(M!f) 5 138Y..IIB (67lE.) 4 136'X.l!7 ( 6<'I ~ ) Helght (m) 110(009) 11)9(0 ·10) \'/eigl1t(II!11 77 (1 5) 84 (14) 80dy nl(JSS Ind Cl fkym ', 2f"i 01 13 ·1 , 19 ·7 ¡7·2 ) Sp lrometry FEv.ll./S J J !: ,¡ IO.AO) 1 ( 1,11[,6) FtV, rx predk;.ledJ fVC (l ) llw:\(l 1i '1· "'1 1 11,) ', 11 11 1; ) J'I (I 1/) FV C1'" DfeOlCled) IIItlll 11111'1) FfV,¡rvC(%1 HI) 1') 1 "1 1. '1 ) Tatil lll m¡¡; capacity (L) r, Oh I1 ,t) ' ¡.'I r' tll lolallung capaclt)· ('l{, pteolcleO) 1·) 11 \11 ) In ' p nl ReSiO\.l~ 1 yo lume ('110 preolCledl 'I!'(ll1 \1 , 1. 111 1 R. .. I~ · Pa l · s ') G,./ kPa fs) O I IIIUO.U 1 ~..t l tll .,, )( II ' I/III.':¡ ., ,'0) 1 11 •1 '1 NO,./Parts pcr bIl P100 I S '0 · '11 ' II¡.I" GAS tr .. n lle r llLCO r:o:. predlcled) 961 11 ) '.¡{,,01¡ IfCO llo preOICI~) 971151 \0 11 (.' 0 1 fVC=lolced e_pllato:y VIta l canCK II)'. Dala are mean {SOl r.xr:eD I whr rc 1r~'1o <~r'\ 1 o:nerwise, Table 1: B as eline characteristjcs had lo be within l 5% of t h ~ value ob t ained durillg lile scr ce ni ng visit. Participant s h ad a sranda rd bre~lkfa5l 30 min befo re drug adm ini st r at i on, an d ah! a standard diet for the r est of me day. A venous cathe tcr waS il1S~ft~d i mo a fo r ear rn vejn of eac h arm in a ll participam s. At 0800 h, we adminis ler ed 1 000 Il.g inh al ed tluli casu nl.: pr op i onate and imravenous pla cebu (s(.ldium chlo r ide 0·9%) or 2000 ~ g inhaled SDP ¿tnd 1000 , .... g ;nrrave n uus flutica so ne pr opio na le ( in 2 mL of pr opyk nc gl yco l). Thc m et hods of adm ini st r atíon we re identical fur intra ve nous (rca tm ent and pl acebo ur inh al ed trcatment an d BDP . T hc infusion was adm inister\'!d ove r LO min wilh l.h t.: <:lid uf a sy ringe driver. rnhalation trea[rllent was taken in a s ittin g pos it ion. During lhe firsl hour af t cr dosin g, pan icip ants r ema i ned in bed . \Ve t oo k ven ous bl oud samples at base line and 10 min , 20 min , 30 min, and 45 min , and at h ours 1, 2, 3, 4, 6, B, 1 0, and 12 a ft e!" dosing [O mea s ur e pl asma co n ccnt r atio ns of tluricasol1e prop ion ate and cort i so l. Fo r lhe n c.::xr wcek, parti cip ams crosscd ova to the oth er ru n .. in tr ea tment, al1:er which they re turncd for a second pharma co kin ctic-samp l ing day . A II st at ic and dynamic p ulm onary~ fun c ti o n tests w~re mea sur ed wim a V MAX22 sp ir ome (er (Senso r ~ \ edics BV, Bilmoven, Neme rl ands) and a body b ox (Aurobux 6200 OL, Sensor Medies BV), aecording tu ATS recomme n dations, Carbo n -monoxide tr ansfe r factor \Vas assessed with Transfer Test (J\ Aorgan Ltd, C ha,ham, Kenr, UK). In additi on to est abli shing plasma co nisol proftles 011 sa mpl ing days, we meas ur ed plasma co ni so l cunc entrations at 0800 h and 24 h urinary cor tisol conee ntr at ions at the sc r ee ning visit a nd on (he ("\.\/0 samp li ng days (ie, at a stea dy s tat e for Ou ticasol1e propionate 500 ",g and BO l' lO OO ",g). A II bl oo d sa mpl es we re d r aw n int o hep arini sed rube:s. They were immedia tely placed on ice and ccnt ri fuge d w ithin 30 min at l 500 rpm fm 10 min at 4" C. Plasma and ur ine sa mples we re imm ed lately frozen at - 70°C until assay. Ma sked ana lysis of pla sma and u rine samp l es was done at me Department of rmernari on al BioanaJysis, G l axo \'V'e ll come Resea r ch an d Devel o pment, Wa r e, UK. Fluti caso ne pr op i onate was isolated from pla sma by sol idpha se eX[[3ction ¡¡quid ch r omatog raph ytandem m3 SS sp eerrome lry (L C-MS-MS) that uses thennally and ' . ', fl 557