FOOD& DRUGADMi?WSIRAXrON Offioe . 200 “CaStrefxS.w.

% -
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9
3ixly24,1995
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FOOD& DRUGADMi?WSIRAXrON
Offioeof q)eoial?writionals
200 “CaStrefxS.w.
wa”hingto&DC20204
R&
.
.
Notificationof Mention to make a Statementof NutritionalSupportfor
AZO-CRAIWERRW CranberryJuicePowder CapsUIes
Pumuant to the~i~~plm@H4timdMumtionA~
of 1994~ @13EA),
this Ietterrepresents
riotiiioation
thatourcom,paqyintiniis
to-makea statementof
nutritional
supportfor ourlzO-wNBERiY&psules.
.
This statement will readasfollow Qanberryhe/ps liocktie aUachment
ofE
cdi bacteriato the m-nary Mu&rwall. u h additioq the label will q
a bold
disclaimer which will read5?WsszWWenZhaSnot
been evaIuatedbyfleFd&
DnigAdnin@z2tion. lhkpma!iut knot Mencikdtoa?a~ose, treat,cure or
preventaffydiseqa” These statements
wiflbeaddedtithe -paOka*
a
representation
of whioh oan be seen rnlhhi%it f%
. .
The abovestmctumf@ctioIIe
.
is supportedby thefollowinginilonnatiom
“-%.
- Exhiiit43:-Paperentitied“Redqct@nof13actmiu& and-hmestion
CrarIbemyJuioe~ J. Avorq et~ SW~
751(19!?4).
&hibit C: Papq entitled‘hhiiition ofBa@&l
‘
E&i~itD:
AdhererlmtbyCmrbenyhiax
Potent&dUsefor the Treatment
of Why
Sobo& J. UroL~
1013(1984).
Tractlhfkotions~A E.
. .
.
Article preprint entitled “Cranberry- America’s Heal~
Siciliano.
Uassadlusetis:
aofado:
Un&d Kingdom:
of
Fruig”A A
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11 SW S@MCv4&jrrL MA01601- (6t7) 933-2020
FAX (617) 933-7992
561 Cmi.ecence f%ce< G&lea, 036040i
* (303) 2714300 * FAX (303) 27W397
-ex.
Tanh. Ctwshice CI+3 6JF. UK - 0629-74151s ~ FAX06z9-7#456
Tatxh $%ncts
●
LE-T3~
*
mlibiifwi&d’’~Jtiocati~;f” -
IMiiIiidi
m?=aed
Type 1 4nd~Pmnb&tedBchwzk7@//ti
Eucayotic.Gll&”
~. -et
4 Antimicn)bial&entsand@21110thCll&#~
92
.
(1989).
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ArfhurA Sicihano, PiLD.
ExequtiveVice ~den~
M,s&
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Enclosures
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Inhibitory ActiVity of’Cra&eri=y Juice on Adherence Of TYPe”h ana
“ - Type P Fhbriated
J!Zwherichiu dim
Eu&uyotic”CeIIs - ----.
DZNAZ4FR!Kf/ A
OF&.t
~
fUVKA AD&t.= MAfUSOLTOCfN0.2 ANO NATHAN SHARON*
.
.
Dt!pamwl qf&altan A4krabWlgy. SiKWcrFily
qfmdd%le. Td 44$* uuiiva~u:rclA&”:’-aid
Dcparrntearof B@hyxics. l%e W4maau Ja.wtiuwqfSAvKV. Rdunwf.- fxra+
~
Ykeiwd
4 AUK J!#tWxe#
faidbitkm of imcierfai adhemace le f&dder cei(s has ka
asdibcd
40 crau~
juice
and Cmlabcq
juhx
k Oaoiw 1*
.asmmed
CO acoouat
Cocktdl &l Che prwcacioa
ofudaaty
fix
(he btadidd
u-ad
hkdioas
adoa
(A.
IL
I31:IOI3=1O16.
W4L W hatecxamkd Ck ~~ ~~
~
~ju~
au * =~~~
of &ckuiit&I d
CX@SS@ surfacekcfiaisof dctiaedqar qxcifid[y fO .yeas’& fiSSUe CUttUIW Cdk.
of Uti-~
tr@WOQ?eS. WId MOUSC fUTi(OA~ UUiCM@Ul&S. tilljilb$ cockaif iahibittd tie adhcrencc
S#W
and P fimbdae (~”fic
for a+-Ga((l-41-@-tJ-@]
but
koiafes expI-&ag t}pe 1 fimbriae(maimose
fsoia(e espmssing a CPM adhesia, The cocktd also &ddbkd yeast aggkIUmttiOct
4adaocfT@oaad&r&ai
by pld%d qpe 1 fimbrba W Iahibi(oq acddtyfbr qpc J timbriakd&i cofiwas diais=w ~ ~~d ~
ascribed(0 theftwke prcsm in fhccock*i&thissugaruasshowf/fO asacck astne@4 a~mide
in iaidbi(ing
fhcadherenceofc}~ I (imbrided&(er& The Wdbi(oryacfh@yfor theP iimbrkkd kCti
oftiw badetia UWI &e axiclaiL CraabcrryJuioL
wasaoaddjzabk andwasdeused OIlf~~er @ncubat&a
orangejaicG andpiaeapple$ikcakwfaiaibited adherence of type 1 tiqbrkted& cd?.mos(likelykaw of
tick fmckwccontest.”Howmr,fhcwv lattcrJuices
did notInhibitchc.Pfimbrhmdbagcria Wecondwk
tOeucqtiutcrard)cqJuice
coaCaias
atleastw Mibitocsoflcetinaediated
adhemw ofuropafhogcas
Inhibitors p@ 8 rok & viw.
CMS Fmtiwrstidks arc reqaked [o csfabiishuiwdwr ~
. .
—SobotaJ:
.
UroL
Baaaidadhmacc
tomucosaiaik
isaaimpofumacp
(hcadhueaccoftypclfimbliMcd Ed.
has bcca amply
bl thedcvdopmuuof infkctioa f3J. ~
danoasuatcd. espe&Jiyf6r4aftWy Uwt iafixtioas (19.X.
10
sk
* adkm
of SMIWktdii
~
by kaia-sugar im~
~. 31L makcdas orcarbohydmlcs might
Sufwoa OffoodsConcainiag
dkcf the infkuioapmccss (I& 2$J.
llIueisaweallilof
aa&xaicvid@CeA%ii
asseYCml
-win.
oa*u=of-bemjuiccaacf
CIaa-
C*kri
ails ~ mcdii(cd
ewecod@lfordJc
plwdoaofmuarcat .ttac(iafdoas (4. ~. 27.SJ. fa~ auetnpt@ &ui@ the
=~::pw~-k-=
ygg’g’~~
.
-
dlhcochcris&
nondiiyabk Subaaaa (Orsubstaaasl Wflicilinhibitsbiad.
ingof P timbrkd & &i.
.
MATERrArs #al METHODS
Juices Cnmbcrryjtdcc Cock* and Cm$bajguicc @a4e
from * Am&au aaabcmy. Vacxi%fwa mwvcqwal
spcayChnburica
Inc.The@or
*W Obfaiacd finalOcean
cohscicueacs
Ofcmtlbenyjuia
aregiucOsc
ash fmcwac
fl%kchdcadd(LI%J, q(daicS@ ~l$?L andtWiiC acid
(osfLcraabem’juia
CoCkmiiisa=ati&w
Uatiwjuket
owhichgklooseaad
twoseimf-am
Wa@Soffk+cdddadtohumaa buaaialad.urocpi. tooweWa@s
ofabout7aad5%.
~Y.
~
dtdidceklka(ndaauscdbysotiotaw~kwcvcronot 4scorbk
add(00.3?
mdml(dmma-to*
dc!iacdwiihrcspcu
(obtypcoftii.fkyxtiw
fnaaufaaurcrand
rdtreaa 17j. Omngejuk and pkappic
-~*e$wwidu~kcflmbri=Jzcd?
JfioemwdmsedlnaMm_-fl*ti
b * qIoSfrequent
.Udnary
iaokwfiwn.patk.auwith [email protected]_tilM
dtWYw MdOUa9j..vi@~ d[&&;iOh~
NaOH. Forsomc dthcc%4%!ricm=&ti
Cockaaiiwas
capable
of Cxp@tsdng
a maaaosc4@k
widl(ypc16mbria& which mcdii&st&a dhu’caaoftiu
backria to uroepi(hdiiC4S (6 9. S3. In addi(ioa[o wc 1
Mxiac,InoS(
p@or@lrik)gcnic
isolatesOf&diexprcss
an4aU+4]&Gal(ahbrcviakdas oaKki&spccMc kctifl
asdated withP fimbiiae.whii aiso audiiws the adhcrCae of (hc,tycria (0 Umcpichciiai&lis (22 Mi (au sugars
qc Ofiilc D &i’@uratioa). We therefore Ua&IIOOk (his
o(’cnmbeny ju-ke ar.
iavcsdga(km (o examine the. ckt
cockail andk comiwn[s oa t@ atdheremx10 eucwyixic
co[imcdii(cdby type 1 and [-w P iimhriae. As
h (hk WpO&dIe i~hii[o~
efk( OfCXid~@@kc
alfs of &
.-
diiyzcd agains( phospha(c4udWed saline (PBS: LW mM
?&Cland 20mM phospha(c. pH 721 iadiiysisx~ti~a
CUM’poi ( ofMw L~.000in the coid far3days
3 PBS. [n OWr cxpcrimcafs. Cite3 * w
chan&S
~mikriy dialyzedzgai(w dktiied water and @pid7izcd9
Ba~6 The E.cw!istrains used are listedin Table1. Thc
bac@a wctw-gnwmunder coadi(iomsoptimalfix the Wducha of their suflkc icctins. Type 1 fimbriadb@*
war grwa InUyp(icsoyhnxhundersadccondhiwM
3TCfw 48 h. Af(cT hf~ fwvcs(cd. the bacteria**
-
washedonce in PBS and suspended in PBS or in (he lti~
coaccntrat”bao(f’+-~~ aIiS’Fer ti~ad... . . . . . .
~@cI@oa adherenceof’&cvditas~~.~qig ctl!<-isdu.e--- 3.0aptvztideiisiylof)l
=------iti$to
uniG’.lrWW@do_nKal&~fi-.-:” ““-”-(o (WW
(or moreldiflercat comaituen[s. One d {hew k (hc
$ho~
fm~osc present in [he juice and the cocke~ti. \vhich inhihits
.
“ Comcspi;dk: w(h<w.
-
Juice (ott
junior spectrophotamcte
rx(.S40 nm. P fimlxia(cd E. cdiartd
E. cdi CFAd were grown an Cwswnirm Acids ycas( CXU2M3
a.mr x( -77T for 24 h: (he hacterk were collectedfrom [he
qyr into 5 ml d i’BS. wxshcd once. and suspended to :i
. .. .
..*WG
1. Lwuucaliasuscd
&l
.
dbhwul$
.f%hfau
&+a
E
z
a&kr
“
@&oIiH-
0iH4fl
0uxkH4
“06
iiarri&
(m
Dian+cII
.
H
%7
=2
mm
EKE
07&K *12
0LKH7
Lz!nmyde?idw
“- MardUa
J=&kfhwi16.4at
H. L T. Mohky(224
JJGoWW(16.4UI -.
L G.W(GW(M.4at
H. L T. Iuobky ml
H. L T. Mobky4221
8. L EktsmhI (14
Q. G. Ewms {U
T. fcoIhonca (IN
Tj’pep
. “-. “..
. NFA
“W&c:
I
.
CPM”
T}pc P
-UT% tkiwualaiutakla
‘Attcrscdd
~ia&rowdfsu&M
cxcqNIHE-l@32
kulwuI6mhr&.
ttFA.
Nodidwd
. 4?duwa.bkod&mqt+ueilk
amoentmtioa ofl.S x 10WCCIIS
perml (3.0ODtmiw inPBS
ptwiously (241.I’k tate of aggrwxiort (Changein transmhOria @c Ustcdjuii
tanccas a functionOftimc)wasCakukd fromtheUmgcn[
~ltimbrfac.Type
lfimbdacWc-rcpuri6cdfmm&cw/i
of thesaxpcstslopcofthc
cutwcpmxkcdbrthcincmascia
346 by,tiulcthod
of Eshdatctal. (11). Thc!ilnbtiaf
light ttansdtancc as a HI{ of aggmgatc formatioaafkr
~Oa
was dissokd in O.WM Ttis hydrochloride additionof 10to 20 @ of the bactaial suspension.In each
MT’’(PH
7.0)to a concentrationof~ u OfpNUCia
pcrml
test the acddtyoftk bactaia in PBS W= conddcred100%:
‘ as detamincd by the methodof Bradford(SI WI bovine
Usual[yit Was7 to 14 Uimin.
TheConcentladorlsof test
scmtmaRiumia(Sii Cknica! G.. S~ Wtk MO.Jas a “ inhiimrs neededto g-vc SO% inhiiiion w- cafadacd
sand+ To obtainIxwragglatiwing WXMW.the fimbtid
fmm dw Encarcurves of inhibition as dcscrii pwiously.
pm#atmn was emss4inkd by addingglutamkkhydcco.a (lx.
finaloonccnuatioaOfo.s%
for10millatmomfcmpcraum YcascagglutiaackmA@utination was ~ffOIRICd
by mixIlssucculel-bcald!n dcdiliiuscdu’creylmousc iog30fdofcnxs-litkxl&nbriac43S0pgo fprotcinpcrmlj
dmudcOltcXtumorccnsandUdncschamstcr
ovary d~~&~~(03_ofPBSlaa~#tie
CO) OcllsfboChfiomthcAmaican~Ctdtute
Cok&
thcmsultswcrc sc0redvisuaUyafkr2mhtatmomtcmpcram
For inhiiiion assays. the yeast cells weresuspended
tk&lW-gmWnin
Ls-mm~Wlls(in2’f-Wu
aCalidmplatCx costar, (3unbridge Mass.linl mlof
in sclial ditutionsOfcmnbcrryjuicc CockaqiiOrs%fructose Eagle minimalcsscagal mediumsupplementedwith 10% aad the hO@tcst
dilutka giving compkte agglutktion was
fdcdfscfum.
LOM l!~utandnc. and 40 U ofpcnfa~m
noted. Each q“mcnt
was done in tr@icate. ‘- ad40pgof aWp@m@npcrmland blcubatcdaf37Citla
Haa@@kdwtcs&Toacriaf
wofoiddiWoas&SOILI
MlddMcdchospke of3%CQiaairfa48 hf39L
of the baetaiafaw
pedoa(stdngwith
LO ODtmitslia
“ 42xdklWmWlaycmofl&cc
aapcrwca WWWobtakL
S6-Wc!lW=shapdlnicmx
WioaplatcsWete*5W
voIuincsofa2% sqcnskn ofaythmytcs prcpamdWm
Moasc@Wdaaacropha@sRcsUcntmousc@toacal
tkshlydrawnMoo& Fortypclfilubriatcdbactcrkguhlca
mc@ta&stvcmobta@dasdcsafRxdckcwhcmf2kThc
ccJfaWk2@edis@@ed
&lvcffsof@6-tWlplas
CkmkxldilllPig q-=
w n iodkator CdlgorxoUK#
tioa@atc(Nuacfo@dm A/S Ntm Roskikk Dcnmar@
bactcrk human @ouPAaytkxyM
ToCachWeWO#doflhcmacrophagcs(sxldccnapcrd)
n2suKsWc@et
WOCdCdv
isuallyaftcr4 st060mhlumom
waaaddcd. Tllcmoaolaycm~iWuba(cdat
37Wt’br30
Ccmpmtm% ill aocncCxpdmcnw hcmagglutina(ioaWas
salllia8%6qatmos@m
lllc sqcmuWnts Contafnfag _ofJaK#ieWmtiwM~ofti*~OD
thoaoaadhcnxttcdsw
cremmpvcdb
yaspkdkandthc
uaits)uith 20(dofkunangrouPAcvthmcP(2$f@ti
lnowkY=ofChcadhaent
ccusconsk@ofmaa’optws PBS). Hcmaggfw”natioawas stxdcd after 3 cnhaof hodvumwMkdtkctimcswichPBS=CaMg(154mMNaCL7.6
zomal shafdagat mom mnpcrwctm
ttd434@[email protected]
Id
Lakx beadscoald wkh
Cat-Gal beads aggktdnadoatbindingOf(hcbacteria GaLOal(Bach-test: Kabivitnltil. Swkholm Swhl u=
B#fgq).pH7ATo block
t.ochcplasti qthcmaau
Wcmincubaccd uscdasa fcstki( for Chcassayof Pfimti(4
&cvfiaS
* 10014ofl% bovinescwm albumin in PWCaMg pcr
*[email protected]@@l&~c~d
wtlIat37Wf”30 nh in5%(X12,and the supetnatantswctv
SWw pfaccd O(Ia slide. An equal VO(UMCof the
asphlcd
a@ @c.snk6 jus( bcfomthe bac(etialsuspension
bactcrid SUSpCnS-kXt
(3.0 OD unitsl W= add~ ad ~~
Wasaddd “
withdtc cad ofa (oo(hpick A@utination wasmcotxkdafkf
Mm
at wm (cm~tWV.
YcasiCggregati assay.Sadioroqvces eivds?ae (bak- ~ mhtof *M
Mk~(*m(wdM*dxlo~@lspd
BrandslnG New Yotk 14.Y.ICCI(S
CS” X
~
w ~
in PBS to a conccntratioa of 0.S c@nL
ofPBS1.
utioutorWithinhibiiom at the desiredconccrt~
ciom added ia duplicate to walls $ondn~
YeastatwwaCioawasmoaitomdin a pawn Awemnetcr.
.-’
.&scli(wL. ...tissuc.cu{tum-cc!kzmdkubatcd :if 3X for .30 min..~~.,
X03fpaytofl,Scaf%omugh..
... .
.
j
.
.,
zAFRttu &r
$4
-=%.
—-
.-.
AL
.
At4rfuuRoa.
... .
Aos?as ~
supemauws were decanted and the monolayus were
the bacteria W(II cranbc.ryy juice
CO&d dflutcd u r~washed fivetimes w“thPBS bdbrc they weresukd with Iowcd by washingV/WI PBS did not atTm their yc.astGicmsastak IIK ceils were then examinedunder a light aggngatingam”vity (data not shotvtd. suggcsdngthat w
~.
and the pcmcatageof tissue CCJkwfkh bound inhibimr acts as a kaptcm As dqnmstratcdW=ththree
more than 10bacteria
&r d wasCakykd. h clquli- strsksof(ypcI fimb(ia(cd& cofi(334.-W andCSHSOLthe
mcntswithmacrophagcs:100pJ of the baaerial suspension rnhibimtyacdvjtyis dose dependent inthe rangeof diItions
(IO%d wasadded.in dupticate to each wellcontahing the
assayed@ii 1). sincefructose(-m) $ndghKxMc
(-7%)
Ofthccodaailf17)andsinceboth
-we
m-ye=
l%c mkmdiiutionp!ms Mae then amthen@orconstkwnts
kept on icefor30 mh The udxxmd baud wcmrcmoti
an? ddyzabk. their C&xts on yeas! aggregationby the
@=fhMiOn f~wd by thm wisheswhhP&l~
To baauia uas examined. It was foundthatglucose at a
CStimatethe numbcrof ktaia bouti themonohyets-kfe
ooncemrationof S% was not inhiiito~ (datznot show).
uwcraoo@perWW whiietheinhibitoryactivik of dilutions of S% thaosc
W
by staik doubJcdistifIcd
foUowcd
byjncubation
fa 1 h at H
tcmpcratumThe
.
1:1O<1.
and samples(5PO
ofcach dilutionwere pktcd in pad dii
on nutrientagar
fw countsof CFU.
lysatca
Wem diluted
(z@. lxv.
m?d
80 -
Rlmn.zs
60 -
ofcrsnbq’jukx oocktdoayess(~nby
40 -
6w16mMa@ModiiYeaa~ti~W@ka
~of~~ca~oftibaaedsd
20
.
.
cotdatcswith thciraWito
Gto-**
liimbdae(24). We fdtia
Edtidw
?& W-ckmalmostcompktclyinhibitedyeastaggm-bydght
stdtts oftypclfitnbriatcd Ecw/fofdii’t
.
$=YP=Cfde2)
aadthatdifutions of@2tok S0gavc
S0%ihhiihioa (Table3).
DifbetIt
lots
offhe
mcktaif
gave
I
..
.
60
shnilsriddbitim(datanotm.
Theinh?biiofyctkct
was
_~Ykst
ticrc%dyds ofthc cockaai!
sgdnstPBS. as
shown forthc threestrains tested (’fable2). Prckubation of
TAELE 3. Com@SM ofm~
Cod@
am.
4Q
20
a&id& ofati~juti
ftucmsG
andmethylainamwW @4Nl on-yeas
WR@CMI by we 1Mxia(cd &.cm?
80- c
60-
C@nca
for.%%
inhihikr
&&, -....
c~
S(r-iia FiUC(OSC “eMN
.4%1
~.
?&sfl
o~<
0.11
4.X
6?1
Diiu(itl
o.av
‘-12
O.ox!..
.Q.al,
. .-,...+?
40WI
O.(I9
(1.lS
“ DaQ [or (ruaosc a-d cad.saii U-cmfivcd (ram Fig. 1: for mcdg f
- * *
VmrcOhlaincd fm *“au&rCfft-+a(n@ sfh-wll.
&
C4S21 %-anoridd-h~for
any Of(hc strxitw !6wl.
4 cdcdwxi
(w (k
tusk
20-
FQb
,.
.8”.0 (25 ..-.{0 ‘(rm—.
25:
loa dikfioo of inhibifor
FIG. 1. (ahibitioa by cranbcny jukc CO&ad (EMand ft-tdo$c
(f%j (+ 10fy~SI
Of-W fmc(wfIrAnt
in[k undilticdc<K4xx?I. {Cl.
~rqy&~
@IE-~o(i~-u(A!.-~ (B].and~U~
.....
.
L
.
.
.
.
.
.
“.
.
.
wemdmikrto those ofchc aamc difutioas ofthecockail for
(F& II.7bc
eachofthe~tim~~d~-d
~doas
ofaanbeayjuice cock.xd,f~ose. gf~
aadmcd@ cealaanosi#c giviagq)%MMti
Ofycast
WWtWWhclkealrqysofsdti
stcdabovem
di&teaI for UKwariousscrams (Table 3!. a phenomenon
-*
~
with we 1 timbriacd cnterobacfdd
*
aJ. NCVCllhdcss.f-cad Ofthe Straks (cakd. the
frwctoscConccauationgiving50% inhibitiwwas about k
$aaacas thatpmseat intiedif~
ofcmabertyju&
CO&d @ng M
inh~(ioa ~d _
]0 Ch
~
of
UUxbyl==aaosk
1[ was S&a foundthatbothCranbcrly
juioc COcktad and a 5$? sakuioa of fructosecompiady
iahibitcdyeast agglutination by type 1 fimbrk pudfied
fromE *346. up to a dilution 6f El(kl.
1
BU&t9faaabmyjuiCC0
xk@
on theadkmnceof *
6mbrfatcd&.agfititO_*~e&tin=
odV46toCbiihaancet-ovqy~&to~a_
CCUS
W inhibiicdsimiladyby diiufionsof aan**
ti&
CoCkladaad by tluCtoscat Comqoading comxatrarjoas
(T*
4). IahMCioaof biiiag of stn@ m ~ ~
jxntoacal macrophagcs by craabGw jukcfkccfmdl_~~
sbn&r@iahiiabytiosc
ti~
tbcjtdcc~
3 Mcth~ a-mannosidc was a@t 10 times
moteinhibitorythanf-osc also in thk assay system(data
Uotshovmk
BiKxtofcraabeqjuicc ~
on hcmaggiudnatkaby
*1 aadP6aWafed&.@ Tlu hcma@ud*”agac@@
d
16mMated E&ff&QfP-d
Edw
a
cdby-jtlke~~~hadaoc!hcloutkhcmaggfm”*@”*d&d
did no(inhibithemagglu(ina(iancaused by the P fimbriatrd
strainstestedfTabtcSL
lk inhibi(o~ cl%ctofthc diiyzcd cranbmy juioccock.
tail 011hcmaggludaationby P fimbrkd bactuia w-astime
dependent(Tabk 6L The Iotvcr the conccnnation of the
didyzed cochaii needed to khiit hcmaggludnalioa. the
IangcrthcPreiacubaionperiodaccdoti The acdvityof theP
iahibiiorIn the Cockxdlwrkd f~m one lot of cmn~
juice cocklail10another. Fix cxampfe. with a lot dil%eru
fmtnlhafuscdiathc~
t dcsui%cd la Table 6. no
inhiiiion was observedafkr30 mia of incubadoa wirhthe
backria. However.afkr 90 mia of incubation. iahi%iioaof
hcmagggutinatioa
was obscwcd. Ia a scpazaxccxp@caL
aampksofthe [W Jotsof Craabcrlyjakccocktaii mcmoacd
aboveWcmdialyzedagak Watm the UoadiafyzabkmaterialWasfyophdizc&and the dry ~~
~
g~.{n
PBS.eachat a coaceafrackmof2 tn@d. Diktions ofchcsc
dutians wereincubatedV&hthe P l%abria(cd& cwfifa30
mia.Whe#astheso(utioatititiM--ww
a ~ diluk the solutionofthc d
kXw= ~~.W
lp to 15 dilutiononly.
E5’kctofcWbeiqjukt coc&azfaa.ggluf&ti
d@f.
Mwsf?yPfimkwed&
.
.
.
Qu&Todaem$p(@&
auythccikctofcmabcny*clo&dmPti*w
.
wiindiibcadscoatcd
@&~@).
Ia~
cFMmbks).Tb
cdia@4j-tiatia*
cJcpuf-~~typclorthcc!FMlwriatcdbsaaia.tihdchtflcrcsukobtdncdktih-~
lctt&thccOckM
iahibiccdaggltKld@
d&b&by
w8sfi14yacdvc
@nsti Ptimd*&*w
.
uPfimbtfWbaculf&a,ad*tiw~
activkyu%.s
oadiaiyzabkfIkbk7L
iaMWoawa$*-fi&
&acubatioa ofthc Pfialb&(dmd
Wfti-w
licecockaa?lfouowedby %Rls(dag
VdthPBS. IMtcubadoa
“3.ABLE6.
EtRclOfpmincubdaaWfch+xmyjukec’ockad
of P tlati(cd & cwf/IHE
I[(2CIaa hcma@udaadag
ac(h~
.
m41cubii
dillu(&id
w
d(ution of inhiiar
PIG. 2!. fddi(ioa ~crimbmyjukx
COC@&’i’
f!ill%d by
lasc&?l( +Jafadherc~.
Of&.&~ta~&ti
Macraphagcs.
“.
. -- ---- .-—-..
.... ..
.
. ..
HemwwnMii
E
~ PA
alxls~
S4
k diabzcd cfc@ka&nt
146
.
.
X32
.
fiwc-.*s
.
d H~
U-Uw.@
+w -
~
A cn—thmcms
. . ....
. . .... . ..... **
&T
Gicdfdqtfe.
sYUlbds. *.wry$lm@@T .y9@c!fuc
.: a#?U@i(ii.a
W4k adnkaaqyw-.m.w.
. ..
. -=
&l -.:
L?MmanKuL
—Aduwmm
‘?BSV.%~*ti
Xffpi’ii~(i~”””.
<-’>
a
.
&
at
—
‘z&uRf Er&
%
——.
“
.
A&ax Cwnotm
A~
.
.
.
.
%“,...
.
D~Q%
.. . .
.-
.~
-
..
Kathisaaldy.tiicdkctitf
clanbcm&oemclctaaoatbc
WM@alcdbae adhanoc of~
d2tltodiikeataug
arsetianhndccUsscxdacdAis
tbundtha(the cOcktdfcoldCls cWod=featfnMbit&&
diaf@Jk [email protected]
didjza&
XtMty.oftimdd kailli
12
o
+“+
-
I1 -..
U?.
MQ
+
+
.
-symb4k+.
auk..”
:ArJ%%r’
:. .
4
.-
T
30
oompomx ofthcoockailinhi
bi(~~-ofthc.
umn0S4@6C {ypc1 fimbriated*-%X
bpkwlike
manner.asassayedby ycaslqWWWt=W* f@W@AatiotUadkmnCetotissueculturecalls andatmdmcmto
mouscpCrhondmamphages-7bcfit@UtfW botbcmnbenyWe_
andS% fiiosc Wdbitedywstaggktinationbypdkdfypclf irnbriacprtxsthatthc tknbriacam
thetargetofinhibitotyam”om
fl is hiiy UdikCfy that the decrease in inh~wqy actki(y
“+
=
*
;:
!
-y?
.
.
Sllwlg~=-—[email protected]“PBswJSumngmdl
@nalM&l@ll&.
.
the beads with the exktail fotiowcd by washing.how
ever, did not inhibit their ability 10 be agglutinated by P
of
.
.“
,
I
.
:
.
i
.
.
fkbriatcd bactaia (data aot Shownj. 711CrnwnaJ con@n—
tmtion of cmnbmy juhx cocktail needed to inhii the
agglutination
of theGrd@-cma(cd beadswas dependent
on
thcpmkuwon
timeofthe baaaiawkhtbe cocktad
CJWe 7J. l-he longer the pminalbatioll rime. the louar the
cOncaMon
of the cocktdl mxkd to inhibiiagglutination.
The nondiatyzabkinhibitor fm P fimbdatcd G CUUcon. Mm only small amounts of protein {4.8% as q“rnatcd bythcMadfoti mdmd [SJwkh bovine serumalbuminas the
Stand@. The inhibitoryactkity. bowcvcr. is heatqabk
@0C30min)andisu nrdRcMbyinc
ubatioflwithwypsin
@kUymekubstratclatio*30 mhl,37Q ym=a$g
a0MI?~30mimmixntcmpmurc.
makchhighlyunlikdythat
-inhiihionowisducto
an.cazymc.
Xddbxcolpct
ofcranbillyjuktandoth
crftui(jukxs
-M%
Ofawexk%d PkappkjufccWqitcd
-WWionbytyw
ltimMatcd Ecofiinamanrur
sbnlkrto thatofaanbcnyjuicc C0cWI(Tabk8j. most
w@w--lfUlmwoseam@lLlxutiowflQ)of
- =q@mwpkjuiOh
howw. did nothddidtkti
utuumoaofGa14albcadsby Piimixiatcd baaaiaor
tbcba@tin@oncauscd
byEcid7~=M
kccin.
for type 1 timbriatrxlE cd after diiysis is due to volume
cxpaasion. since even at a dilution of 12 the dtiyzed
matuial gavepoor.if any. Mdbition. W-S
* dihnioa of
cranbenyjuice cock7aIY causins 50% inhMkm of type 1
fimbriatcd& mfi was in the ntnge of.l:E $0152. At such
dilutions. mnbmy jukc cockzdl “titdns 02$ to 0.1S?
fructose
asCrkukL(cd
fmm the l’qxxled dysi$ f171.crankry juice was also inhibitory to t.ypc 1 E. di. moa
bably&rausc of the praencc of fructose in the ju”~
rdad. theConcaratkm of fructose nqlimd to inhii SO%.
ycasi aggregationby the bacteria or attachmem of tie
baacfia to macrophagcsw= also in the range of 02S to
p.1%
As shownin Table3. fi-uaosc is about a 10times ~cr
inhibiiorof type 1 funbriaethan methyl a—mamwdc, Fruo=
COSdWlSShOW71 pK’ViOUd~ by Old ~6j to ~iis~
1 iirnticd SafWneUazvwhfmudumand Sfa&eWlexaaf.
Subsequently. W.+
@tsc.hW
001 found that fiwaos&
inhibhshcmagglutmmon ofguinai. pig c@rocyxcs by
puriikdt~l funbdaefimrn&ooUandt bat@sinhibRq
activity of fiwaosc was 7.5 times kss’than ti ofmahyl
●
05man*avafucinag3txtnc.tktwithtfxob@ncdbyus.
T&kcnto@hcr.
ourdata
showthat
mostor
dlofthc
WbWon ofycast
aggregationby thccockmilorjukck due
to the !&we
contan8 WlwvCr.
preseatinthecaktal
a!thougb &cOse fs
laiaboutthcsamc coticestption
(“mLthlssumrdOcstaothlMMtthca?sre@koofYc=tbY
thetypcliimtiiatcd
baacria~ only%ttirlowdeaifai-
-f#L-—f&@m~
juiiCocktdl
atsigrlitkant kvelsare
tspmscbtkraclbcrly
qdnk acid(003%).
citlicaddfo.3%L andmdicadd (o.w). mcOOdd*
a7). Ncatrabd soktions
COntAins
vitaminc (032mghnl)
of these oompmds. atthcoonoeati
Wati&d
not Whit yeast aggregation by type 1 flrnbfia[cdE d
1(datanot shown).
The Coc@il also inhiiicd the P fimbdaWdt12coli.-as
mssayedby agg(utinatkn of humancnm~a
ad of
[email protected]
fwo~
l%e inhibitor for P fimbriae w=
3ondiiyzabk suggestingthat it is of fdghmol-w *L
~S *i@ is dcpcndcm on the lcvc.1 of the inhibitorand
he ti~ of @wub@cm of (he bactaia wdth@ o@k@3ddencc that the inhibitor is adsorbed by the hc(@ ~~
b obtahud. since inhibiion we< observed even ukfl
duibitcdby
Otan@.. “..L6
...- k
-0
w
100
3.7
S3
-S.S
31
0.s
92
0.6
90
UaabCnyjaii codm aa avazgc 0( 1.4S$7.&&..
W rcpord by [k ~=.
&
&ckw
G (k
matins
a w4a[ of 8% su~r.
~ wfi&
<*
is (M*.
- kzcli omngcjuia
juicecofwim 2 KWal
of 4% rcduckg supm. of WfIid.X is
4 Pincappk
fnlmsc.
.-
the fnhibior is defined. it is too early-m spccula[c on the
mechanism by which h binds (o P fimtmated E. co!i surfaces
and in(d.xcs with the ability of the P fimbrial [cc[in ;O react
wi[h GM2d residues. Moreover. at (his s[agc. [he
...’-possibil-
*Y
a
Chcndndia(yzddc
cmsciai.mmt
m+ iaht% adhcr.
asoc audiicd hy~
UCAdC4L -
Rqauion Ok&’
OchcrdualP Gmbrfac
-(mot hc
.
.
mia kt&doax
& E. M&l Sldcc
wbhdma(csHl$mchii4dby
h(ocfdagfJmcdltf+b
cabaf~mar+amd+fh
*S3.
~~alalwla&uafLL4m4w
.
U9L6.
m4aan&&’.
10. c&dauak&*Aad4.
WM. hmuamta h?h~
@wacesdlumaaki&uJ?.&<
W paiz--%d
‘E!%&.!ta.%i
.Ear. A 4XL Ja8w4..qq.
s ~
mm
a?OCWitbkhibkxysugaccCL
3.%J.’f(&b~
arHA&dsHtcm ui4&i%2$%i%2
@~ti$msum@Mottd&af@m&ot
iksafcL”uss@131&
baaddadhcmpc u@iIcafrixcdlc
M*~
.. .12 maG&P.am.+&.E&JcyD.Gww
sob&a aa who taredW ShcCrarIbcrryjuioc
and
tkwhmdw ~
sLGw6adL.197s
ikciae
“4aodadinhibicuf
bai@caadkracc
.
aiandadw&h+tukaocia&dmwi&fdi-tmw&detbr
krmahl fda% lmmua.s&65&667.
dddd d“ xuggcsd(&athy ~v’%ib:.~~~
W%-uc&LOCcQ
nd. Uumnul~~~-WL@
adumnocloacid
coionhion
of muoosdsurf=
N amSk
i%i(yofsbc W6Kckcdn$of Edwddua
-Y-k-tidtitititi=tsckher
putum@&cand Sk&biid(a @dnt4dk~@.
Rcs.
iaChcguL thcsounx ofmosaumpadmx
orln(hc
ldadder.or ac bothsites.by preventing
adhemnrxCO“imd
$@=W=~~w~timm.byEtisaxdas
WWlmamKS5pdk andGakGal+peCiiklecd~ The t’ma’ modeof action.&CWnpa[lwc
Wilh-lhc suggestion
[M
Cra@eny ju”~ cocfxaiimay act primady as a prevcocive
agent in uriaarytraa infmioa (3S/.
In connccfionW.(hthis possibility. we should consider the
information
avidfabk on the adsorption of fmc!osc in [he
alimcanaty ttau. This sugxr is gbswbcd much more slowly
$han glucose (7j. ~US. since fruc(osc is present hi the
-I
a( kvck (hat arc at kasf 10 times higher than those
mquked b theinh%ition of type 1 fimbriated& di. it is
cmodvabkCMinhibhory kvclzof the su.garare a((stincd in
the colon. where most E. coli kiidc. Funhcrmore. i( has
“k
shown that a diet rich in frw(osc may result in
$ec@oa of ftuaosc in W urine Whether or not the same
ar!gumcn(mayapply for the puta(ivc inhibitor of P fimbriated
loctht snusl awah fqther swdy.
.
Ancxhcrpossiiitv is (hatdritiog cranbc~”juict coclisaiimayaffca the u~narycoaccntratio~ of Tamm-I-Iomfall
$Ycoprotckwbkb
is known to interferewiththe adhcrcncc
ottypc 1 E. cofi tohumankidneyCd[S (1OL
Widiyconduaed
clinical swdies arc required to cstab~
u+Acr the cochai[ indeed functionsin vivo and
whcthcranyofchcabovemechanisms
is opcmlionzd.
C&2..-
uFrdtlu%
cs=9J. Af0Aldaa4a
J.R9 uunau&ad&L
EkcasM&196sGcludca
adyaisotphalscwri
dOncoalrdaf
F~dQ’w
J~Ofw-d.
J.Bac7eriOL
3S Cibbaa&
i~- ad L Dank 19S3.
Asochknoffodkm-m
with humanod q“thdii
C&
&( dtW.
Arch. @d Bid 28&’%]-
-%6.
16.Ca(dhar.
~q R. Pd. R. Zilberberg.
xndM Mm.. MO.
Eweratdgcnk
Eack&-&
d{
(EfKj
isdwcd
in the
Tcl-
Aviv (fsrdJ
*u. Med. M.krohiof.Immund. 16$%?.341.
17. Hung. V- and R. E W-olstad. 19K6.crxbcrryjui~c campoai(iom A Assoc. ~. Anal. Chcm. 6$M9Y--X7.
T.L f’.
Vikaw fLS=- H.WWcrg,●d S.B.
Swnsaa.
1982.
Pen(igcwecogaizkg
timbkc from humanuro-
18.K~
di smins. M--CL Immum37:2%6-291.
pdwgcrtk Ew-kidia
19. Kuniw C. AL 1YS7.tkcct-kn. ppcmion and rna~cnwn[ of
urhuy ~
fnfkcdons. 4(h $d.. p. 140-147. k & Fcbiicr.
Phikdclphii
20. Ldlkr. tLi and C S=nborg-Edca. 19X6.Glyofipids as mcep
cofi,kdns or adh”ns. p. 83-111.
fa D.
(cm fbr.JMkri4k
Mircfmaa
(C&l. Mii
kc(insand aggktinins:
pmpcrtics
andbio@CalXd@. JohnWi[cy & Sons. Inc.. NW- York.
?1-hfii
O- ad L Okk. W&i. Microbial tcctk am6a@@kakw and
nins. p. l-l% la D. h@lmart(cd.j. Mii
~odnhw gmpdcs andbiologkdxiivi[y. John Wiky &
Sons. ka& New Yok.
T- G R CMppcnda& 3. IL Tcnacy. R. A. HtdL
and J. W. Wamcu. 19S7. &xprcssion of (ype 1 fimbriacqa~ lx
pCrSkncc
of fidwfchia
di m [k Cd&CrUCd
ieqtirud fOC
U&wwRECITED
.
J.C(ia.Mii
zk22S-~SZ
uritawy ~.
LAmasaa. k& O. MW@Lsebo&Q .h@cknakXs&wa.
23. hfoa ~ to. 1962.Obserwdi oa the &&ximussofusmbcrry
andL Ok& 1979.
Plewn(ion
Ofcolonkation
OffhcUrharyuac(
juice & u&& infcaia& Wii Med. L 6h28X!833
dmkc whhEMaM&w&by bkcMng@iacMa! adhercncc
- 24. Of.. L aad E. H. w.
1978. hkmosc bindiw ad
. Wid mcthsefxuuulnop-ycawsidc.J. Infcc(. Dis. 49S29432.
epithcfii M adhcxncc of EktlaiWa
cd. hlfca. Inunarl. m
Z~y3Gft.
Cd6QLOfiJk NsfW-OQ.41t16
D. Mk4%%%!%~dh;
awmP@cs Ma. knavm.
2%X1744.
sJ3caduJ, &fL198L 8acHidadhU$rncC
.
Mc$@oas atcdiskul cawhmcntotbs$%%%x%%
smfwCs.1, WcL Dia.[4Y32M4!!. “
4 8odd0P.T0,
&qandi2EL
Kzss.19.59.
Cmr&rryjUke
ad I&aruibaaeriafaaioa of f@purica&LLLa b.c&.Md.
s@81-f3!?.
~ ?976.
A rapid and scdivc
mdhod for the
S. B-U
quanWaWoaof zmcrogramquami(ics of proccin u(i(ising (he
22. Mobkya IL L.
.
X7au
Lamf A. Pcny.19K.Mokcukr
basis -ofmkrobid
aCrCnCCCOsiss
uc%p.7-13.i
lfs.E.wr
gCtl!w#aand
B.
ROSUt’(CL&hfOkCUIU
&&dad ~
a&&m.*.
kmSOddy
(ixMii.
Washiflg(aEC
.%0(4 D. C 1972. Mibhii of &’ la@acdon bctuwx fimbrbd
2S. Of&
wti~
ad c@mcytcs by o-nwnnosc and other cubohyd@e& f. Gal. hfii
71:14947.
27. ~p.&~&~a&C.CCtilW.C~&~
~i
~~k;c?ttmllt
of Winq lracl infcction$. SOuWc$i.
.:.
2& RcW C-A
.
J. D. Sobd 1987. fkctcrhd adhcrcncc in &
fxinc@k oflmxein dyt bindin&t&wLW&cm. 7222S-2S1.
6. Badauuh &S. Fst@r. R A. W@ andS. L fkft!.198!!.
@W
of urinaryw infcaioma H“cu. Rev.lnfcct.
Dis.9:47047.
-W
_
tirdwwfa>tde
of tk D!U seqtunccs
encodingIypc1 pii J.Bacwiol.16275943.
29.Robats$ L B. Kaac&G. fiuenius. R hf6t(b}. j. W-mdbcrg,
~{~
aad S. & .Swasan. WM..Roxpmrsfw oyc~d~u
7. Davcapurf
IZ,lji’.(oM.1977.
Phydology
ofchedigestive
tract.
p. 214-2WWar
Book Mcdic%lPubfders.
Inc.. Chicago.
u.dc-Ma%PqrLGdcrgfmL&ncrb5dqA.-cLarssO%lL
LcMcr.
A.&w
B.?-iiksm
and C Svan~-&Mn. W7.
Rcccp(or-e
aggiu(inadon (cs(s fa dc(cdqn
[hatbindgkbosck glycofipids. J. ~in. Mkrobii.
9.W@+
3.P- W
of bfAC%Xkd
A-lfia rdi in pdnw(q. J. Urcd. f31:16W@30. Sstk L h and E. C &ttsch(ich. 1977. Hanqgkninadon by
pudkd vw f Ei-de&Iiu di pdi. J. EW ~f~. f46:~Jf@-
-
ml.
2W01-10h. 31. Skarom ?4. f9W. t%ckria[ kciins. ceff+t~w~on
ad
diwx. FEES Q(L 2[7:14.S147.
&c(c&l~
~ ~d [.~(ck~.
1~~.~~nn~~ ~p&{fiC
D. C 0(6. 1$$0. Adhcsin<e pro~ics
of
if%k
Ell(CKib2C(C&CC2C.P. i8.~217:‘in & H. ‘Ekchcy ‘Cc&l.’8~C- ““““y+’~ar~”
““’
-
___
—-—.=
.
,..
.
.
.-
.
.-
1
.
-... ....
... .
....
. ...
. .
.
-—
.
Exhibit
1
.-
D
–-
.
-.
Americak HeuftY’’fklFidt
.
Arthur A Siciliano, PILI1.
8
.
- . ...
-...
.
. . .. “.
..
.
Cm&T@ ~am-nium macrocwpo~ V.oxyqccuq Ckycomm
qdipad~j
are a member of the heath fimily and are one of three lhits native to North America
Tkplantsyieldpink flowersfollowed by small, red-black edible kries
My.
hey
grow
Canada T&efit
in the wild from the Carolinas to
--
North &nerica occurred around 1816 ~emy
marshes, or in min-soakd salt meado~~s
from kme to
cultivation in
I+all)and. ceqtered in sandy
in h4assachusetts$
Washington
andOregon. CumentU.S. usage is abo~f
Jersey, WScons~
~e~
350miIlionpounds, representing
retail cranbeny products valued at $1.1 biI/ion.
.
Q143fnist@Nufrition
“bogs,”
-.
.
Cmberries contah about 88% water. Amongthe other orgdc
oonstitu@s are -
fhwanoik anthmcyanins(Odainj,Catechiu titerpinoi@ B-h@roxybu@C .@i&-citic,
dc?
gkuronic and quinicaci@ ellagic acid and vitamin C. They are a good source
of fiber. Acid Ievels are high: pure cranberryjuice is as tart as pure lemon juice.
Raw .cranbemies are fairly.
.T.*
.“”
..
Io\v in dories
oarbollydrates (TI Yo). Cran~eny juics
.(209 calotie~(ound)
“cocktail,”the kading
.,-
I
consumer
-
and
product
-
-~ -—
.!
. .
—*
.
.
Pr@wd fromcmnIxxzyjuio&ooritiinsM-0caloriesper 8
otmoe
stX%@g
p-y
-
‘fioM fie”~eetener,
-m
-P.
~ria
.
“unsweetened
:.
available in.oipsule form (lx caiioriestoapsule).
B&tory
.
-
~uioe
powcl=
. .
k
-.
.,
..
.
4
..-.....:
The word “cmnbenywfirst appeared in a ktter by Q& Cod missionary ~ok
Eliot (1647). -The earliest
.
q-
‘“
desm-ption
of a European wiId cranbeny plant (mamh
wort/fenne berry) appeared in Lytes’ “l+kto~ of Piants” (1578). When the PiI@rns
arrived in New En-gland, the local native Americans had been akunin
g wild
wanbem”esfor centuries ‘a.sa fmdstuff cakd pem~ican, a &rnbtiation of orushed
beds, M anddriedmat “Othertribesboiledthechiedcranbemies
and.stioned them
.
MM maplesugar.TheEnglishsettkm found the sweetened bem”es made an excellent
sauce for meats. (~)
t
.MostaI1crankny saIesintheeady]900’swereof the fresh tit
-..
The crop I&
handpicked untilrecent times, afthou~l the fimt harwkting “maoh.ines” wwe ~atented h the late 1880$. h 1912, MarOUS Umnn began oanning bem”es.zui~producing
-berry
jelly, a mixture of fruit and sugar. During the 1920’s,oranb&y same was
in@odu@ and in the 1940’s dehydmted onmberries and cranbeny juice ~cktail
b-e-available.
Today,cranbemiesare marketed ina w“ety of forms (Tablel).
..
.~_
.
.
.
.
a
.
JW2dicind
Uses
8;
:.
.
-
.
“~~pt?utic appkatkms”of ~Hes
.
d~mented
s
..
~..tichdixlthedief of Wod disotim,
dtuing the 17th oen~
-.s..
.
-[
ailmen~ liver pmblq
stoma@
.
.“
appetite
loss, sw
and cancer.
‘Native
Am~”-
pq-
wound
vomitin~
.-.
.~sti~
-.
from
..
@e tiole
dried tit
NewEngIand
fok medicineusedboiledcranberriesandsealoil
toreduce the sevetityofgall bladder attacks. Early scientists believed that cranberries
beneficial effixts, especially in”uririarytmc( disordem, were due to its low p~ (h@
acidity). Germanph~~sicians
in the mid-1800’snoted hippuric acid excretion increased
...“
afkk cmnbenj in~estion (2). Since it was
that benzoic acid wasmetabolhd
known
“~ to hippuric acid, researchers suggested that the beneficialeff&cts
of cranbem=es
were
.
.
.
due to these antimicrobialacids.
‘Asearlyas 1914,a report proposed that baotenalsuppressionm not related
to eitha
pH or hippuric acid
excrti-on (3). Jn 1966, researchers observed that the
dkts on thepH of urine by omnbenyjuice were trarkent and that acidification may - ~.
,. . .:*
not be theinain rneehanism.of a@”On(4). ti~nt (Ilink+ngsuggests that cr%tenyjuice
arltahls a polymer tha~prevents the adherence of ~aeteria to the WakLlining of tie
bladder and tina~’trwt,
thereby
lleJp&
to prevent
utin~
i~’ons
($8).
O“ther
uses @&anbeny inch[de itsroIe in a reg.men to decrt%se the recurrence of ~W
stones(9) and as a urinary deodorank( 10].
#
..
‘
. ..* --w=—
.
Today,over S2 milIionhous&hol&consumecmnlx%y pmduets The eady
hdod
9
.
of cmiies
use
health is continuallybehg
to maintain uti~~
.
=ktantiatedbymedicalti~andph~-dans
are nkinmending
(xlm~ptiuk
.
“
. . ..
as”anad@ct in avoiding urin&y traot infections.{]1).
-
-” ~
.-
.
‘“~
.
.
.
*
. .. ....
.
.
.
.
.
.
-..
.
.-
.
.-
.
.
.
.
.
..
“,..,.- .. .
-{ ~-
.
..
. ...
. 4—.
“
●
✎
1..
1
2.
.. .
-.
Rmn.wcis
.
✍
✎✎
D. J., Czanbeny 13arvest, Spinner Publications,hIC.,
New
1
E3e$lford#
M&1990
:
.
lbmas,
%.
-.. .
hdarderosi~ /L D. and Liber(y,L, ‘NaturalProduct M@c&-(G..
StickIey Co., Philadelphia. PA 1988)
B1atherw& N. D., Thespedic roleof foods in relation to the
composition of urine, Arch. Intema[Medioine 14,409 (1914)
4.
✎
Kahn, II. D., et al., Effkct of cmberry juice on tie,
American Dietary AssociatioTI51, 25T (T967)
.
. “
~
.
JoumaI of
.
5.
Avom,,L, et aI., Reduction of bactm”uriaand pymia a&r @gestionof
cianbe~juice, JJLM.A. 271,751 (1994) . ...
..
6.
Sobot~ L E., Wbition of bacterial adherence by cranbemyjuice
potential use for the treatment of urinag! tm6t inf’ens,
Youmalof
Urolo~ 131,1013(1984)
7.
.
-
.
%hmid~ D. R- and Sobota, A E.tAn examiriation of the @adherence A@”vityof cranbeny juice on urhuuy and non-urinary
bactetiaI isoJates, Microbjos s3, {73 (1988) .
.:..’
.
8. “ Zafiifi D. etal., ~nhibitoiy
activityof qqnberryjuioe cm adherence of
T@ 1 and Type P fimbriated E. Coli to euotuyotic @s, ktimioru.
“
Agents Chem. 33, 92-(1989]
.9.
Zksser, ELEL,et al., Managementof inf~ed stones W@ acidi@g
agents, N. Y. State Journal of Medicine 6803001 (1968)
.
10.
WalsJl, B. A.,
Umstomy
and urina(y pH, J. ET’. Nwhg
19,110
(1992)
urinary Tract lnfectioos id Ad{lIts,Nationil lnsti~tes of @l@
Publication #91-2097, 13e{Jlesda,
MD, 1991
~.
. ., --W+— ..
5
. ....
.
.-
P.
.
.
&&ly.s4iur’q
.
Tab!e 1.“m
I
-:
-25%juiq
swcctcnas (oom
kcmlcd/’lcd
‘MI or FmzaI
Food
aabcayJukc
I
Yes
I
Y=
Fk%rfivm
M bulls
“
“
14
I
I
I
I
J.%nmqcoloGand
fihcrsoulw
Prqxmxl fixxnconcentrateby
di!tiion
Jngmdicnlfbrdlillks
Fh2cn COnCcn(ra(cd
juice
Ihgrcdicn[ for
Crmhcq’juict
Ctlckiwdl’w$
No
o
“No
4
2%
27
.
!
XKcatdc (fiwcn)
.
mb&yJuicc
P&cuaswxcncddchyfmwl lllpdknt h
llcUlwcPOwkf juicc~canicr
Capsule!
&.
&P4m&
CWnbcnyjaicc,fmially
No
oMx”j
naltdidandcmicf
FoodoOklr
.
ummx@lmlml?M@k Diisq)pkmud “
Concul(ra(qxmxlmti
gclahl
Capsules
-J~
cqxdcs
.-
Yes
rwoc!
I
m CllkC
rarlbq;Juice
Yes
.
urcfmi(
.
1=
‘“
Bmmgc
bdcs
Vho!cCranIic!ljcs I
&d cmbaly
i
I Bmcmfc
-10% juice cowcau
?,
“
Olup)o $@fizaS
2radcayJuicc
Irihks
7
yes
-
c.
32
“...
“48
“
-.
32
.
.-
01995
AhufA. SM&l10
.
“1
. ..
...
... . . .
.
*
..
.
.-. ...... ... . . . . .. .
... .
... . . -;-,
. .
6
‘-
.
-&—
. .. . .. . . . .
.. ..... ....-
.. ~-.,----
--a=@-ra3i#imfsck%
.
Youu@auu siilteuidimi&. Y
‘=w-’mW-”
.-
-.
ABsmAcl’
-.”.
u
.
studentvoIunteerswereused.'I%eceUswereobtainedbyacraping the bud mucommembraneawith a ootfon-tippedswab.
3Eece!kwere tllensuapended in PBs, centrMlgd We$hedl
time WkhPBsand
res WpendedinP13s
Wnksaotherwk
stated. TIMIInalconcentrationwaa &emnmed byhemo@ometlyandacjjdaa
necessWto appfoxilnatkly I(Poena per
ml.
zkctdul&
=WB@eriaI
adherence vfas teated
usillql!modKc@n
“ ofthetechxliqueckdbed by Pamollsand
assotWa’Sampk$(OS mL)conM?lillgl(Y ba@riaand I@
.-dkl==ecomhedandimbatedatmlll
ashaking water bathat SOoacillationa permhtef~80
Inintl Wll%ellaanbenyju keorsomeotheraddi
tiwras.to
betitbe
Ecolilrascqended
inthetestaolutfoa
and
@ncab@fnc
10atdnutea at S7CTheaampk
wastlten
fikereduainga ~membmne
fikerholderthroagb
an8#ua@ycarbWte
membmne fitter ~and
.
waahedwftb30 ml. of PBS*
filtem Wem*placedon
I?iassalick alkwedtodlY andtben remoWd. Tileadhe&u?
●
.
wmluALs
MD
StErMons
&ithetMoasaldbacte&
weretherlatdnedtQitbmed@eni
blueandexamidwith
abtightieId~Ad@mnoe
%asreoordedas
tbeaveragenu rnberOfba@eria*e nltlwIkl
teikAtotaloflS4 dinkalkolateii)fEdiwereti
istdy.llwbacterktwrekdatedihmdiffmmtpde
e
baOkgKmClcountc~sbacteriaper&theresuItswere
td8private
udogkLAnko
lateaQ?erestor
edind&
ceILAtotalofSOcelk
=-oountedforeacb
aan@&kootttd
uunpkwaabzchiedw henbucoalc ekwere~lftbe
ktduriaaadmobtainedH~wti_a
-QftiYoun@Ovm
omiued.*
Crimben3’]U.ibe Three Preparations of cran~~
h of brababe@in!Woa (BHI).For udherenw assqya
ctedaweretranaf& to BHIbrothand gruwnunder
m
lXl&qfor+bouraata7cl?lWbac&&
werehar. used in this.suxly Ij cmxl~ Cock@ 2) cranbenyooncen~
whed once in phosphate-hufI&xf trateand8) fkshlyprqxxedjuk The il@lypreWN@
(PMpu 79 ~ WWKkd to a final concentration of wasobtainedbycmwbhgtheberriesi nabknderfoWbY
g for30 @nutes to expresstbejukm
k ~ MLvu the.gseof a Petmff-Hausser
chamber.
In ceatri@aCionat 10$IOO
Fort&
adherence
a
ssay,
tbe juice waa either used Ml strtM#J
y-*
(wti U’e5
lnonito+standard~.
*~-~lt$+3d’4
5efit40e!k UroepiWM ceUawereobine$fmm
the
ofwomenwithno hiify of urinary
g*at
flxtion.l%eceflawerekwestedbyoent
aifugati;nd
once with PBS. Tbe @let was resuspended in PBS,
***M
ti a fti concentration of Y(Y.kdfsp
hemocytometer. Buccal cells from the author and 3
1963
tedfor pubkatim Deember 19,
~ for reprints DqX of Biological Sciences. Ycwngstow
liverdy. YOungSown,OH 44555
or diluted with giasadistdled water.
Animot.s. Tbemkeuaed
inthissmdywere&ln
A$@
obtained fmm the Northeastern Ohio universities CMlege of
MediciIw &xIW.owW Ohio. AI! ~nti
=
~nd~
with $3rnaIemifewdghing10to ZOgnLThe mii*
mtintdiiied‘WX”tidtmaldiet of lab chow and “%i’k exEiSptZ?IiZF -“ :”
undjktd
CMX&ITY COCktd was substituted as the only sourcTs
of liquid To sampleurine the mice were placed on a sterile
nonporous surface end grabbed suddenly, which usually caused
them to ~oid urine.*
. ... .
1013
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<Nat Cigdkndy diffawd fmm cav.rol.
. ..
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AUMGKLNGG
GUANUEJWV
-.-.
vaf@=~wsarbit@ydividedin40s -&~~
alldcdsdbited adkrewxl?y7speroeat
Mfetbrovera
2~as*conttoL
&gedonofchecockd#
Luuj
ThetiQ”a
resemadiat9bfe& Urine _.m ISoftbeS~~.
~wy-w~
(P,<-J.
Iati,-iia@heauubeny#di4
lWtoellalimWerepk!ed
aabsM@d &?rarin4-ako
%’.
ouaAktkhkh-olxkslIu4ts~**
betwoendae~~
lbilewasmodgawanqdidknoe
#$rad=lersupp&Abraperkd.of14aqy&13@eel100nQd$
dleliscsmpk.
- “
slsrahdthelrs&mud
waterutpply.”4$dsy
.&me&dCttcine
eXxedonofIdppurku4di+eillv@ortd~&
al%ehlghest~
Withtbet%edingofcmnknes
wasadkxed fi7nnthe
rnksfhr6edhemM@3
oentdonofypp41rk4dd
achsewd&lthe8nfne wuQJq&L
mhwIdnewasOdk%edfkuneg$-ll%a
admefrOln$wOm’aspOOkd#dmed&lyM@assdk6uOd4%rKwItdOIMOfh&XXiCddmn@gk_tOw&&f.
W’r@etertedi
ntheadkenceassw
andrloiddbitk~
lgkGkGm dew= usedtar@lCh
huubata
Umepd&d CdIs.
me lemksaprz$-h”~d:
.
. .nledne&Oln Jakeafnkfng
Cmlbenyjaioe
dgammdy
IXSCWSXON
.
-QdhanCewhen
compared
toaOntn31*ftcaa
aIsobe4bsavedthatacine liwncoatauImioewes*_PlwkUs&wxC@tkns
of the ltsdwU&40fCdklg
J&
c4atlydi%’@Mt&MheiWitWontrol&l%emkeulefflQdned inthetnwnMat
ofuciualytractinfactions have foalseda~
oatbeglanbeqoOd@ WK!renornlallyaafve
atldshowedllo tkepotedelofcmbezry
juketo~the-de
●.o@w&ddgrisofstr’es&
Udne==and atheincmsedu rinqffcletiorlof-c
tiastmng~
“C~t8$SOC@d Withthe @@on
~-d~tilmako
aradnedialIunuul ucinainitial
trMswreperfimnedoll I ofcmberryjuke” It was found that bcmases in urine ~“dity
Wereonlyslightand tmnskntandhippulica cMWelyrea&&
a concentration in the urine mxessqy fir batiosfasis of
%%%
commonl.lrinq tract pathogens.
Intheinitkl ~@H=fo*-&itwasfd
diatthe coclctd wasaverypotent lnhibkor of
Cocktaa Colltdnqin
bacterMadherenc&H Owever, Cran*
dsceaLlna2ndserksof ~***--Pfdl
mddidontocmbeny
juiqfhctose
alldvitaolrn casmajor
peroaamftslecIiakalstr.a&
to3h4mrs*iW%th@
WW&tailWrinetaken@0NW&-~@*J=apHofabw%dd~d-Mbe
ndividual&oroollectidy contrii
to the ~
inhlbi-.
kz~emw.ddm=afi-whak-f-tit
ldhemcewas rlotaffededabov
epH2Thisfind
ingisoonisterltwicbtheo&n@ons ofotherinvesdgators.~~l%lc@se
Boneofceved carbohgdmtes thatcan inhiiiadherenc+%=
‘ruc@e was tested at concentrations approximating that in
tIeoock@and was found toinhiihacte!fd
adhemncein
bisrang&Ibwe?e&dlecon
tri?donoffiud
oseto*obnediddbilionof adhemwhy
the~cockidlap-
h@heqwasasedasab
sdnecxmtd.Inasa
ksof6
@pdMIM%atwasf dthfith@eSiont
ilSoancesofthe
coddresdtedin
aconsistentinhibit fonofbact+dticaoAorl thehssis ofthisob5emtion 4ulqNrunen
m~a=~~wgti~dnfemekt=
asked tOdr$ak150amXs ofcranbenycockaild
wasthen sampkdwithinZto3h -
tMruriae
Wfnetaken priorto
.
l?afsto hednhnsl. No@ditiveeffi3c
twesobsen&ercept
heavelyiowco Wentmlmofmlnbemyjdoewele
testedb
mlbhdOnwMht
kdOsehv’&.n&l~atthe
COMwmda
e~~emno~keff’ma~
demfbre&cameappe2e@daatsomefh ctor(6)inthecM.aofthemW%~-*ma—~
Mpdmadlg respondbk fortheirlMMtioa Thkwescollmedwhen kwasdewMtratedthat
purecraakry*
fwasac0mmwk1430mwntrate
orfmshlypmrpsm!,
is a.
unginhibitOrofbctedaI
T-3.
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.
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aa7$ X7
aoA*4$
6.61*&
6
W*S.6
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u“
29.ss%9
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s.1s4.1
273*S
4a4*a
.
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‘Nacd@alldydifkmltf
iualo
JllcmL
W@kuaugdiau’eaitfiam-(
p<ulh
.
?e4ttdUciIu
SzZ
OIMml
Mix
ruled urine
‘
ra9*4.9
WO*I.7
S1.45 7S
~~ ~ ~~
40.6s 7s!
38.4 z 7.4
343*45
“21.2* 2.9
36.6 z 4.6
ml&
3.:
~
“e Scmw3wlEmx of MeQ
“ Signifkxndy di{krtni {mm conwd (p <0.051.
:.
P-=d
the
mos
Urildng
S.J%!227=LW2T
=fmi’&
of
d
haence
bbibdoninaoessofmpercentm~
~yy$y$~
“4a#&mtbeMlowing~
* agrdk!e
dmrpoqent
afEyL =,&slda&R
~-~*-=kYM-muMaMwted
~awMtlgofthellcdiceusr
eamedthenollrid
adherwepsttem,
a)addition
of
t
hejdcetoqpwd
*pmaUded
Rcolicaused arspidmkasq4)arft,ureaf
w~r,he~
REFERuiu!s
tbelloo
liincranbcnyju
kefaahoum hadnoeffi?ctorl
@wthorperuwnteff’ona&renc&
OlleoftheproMemst@tmsyhe encountemdinthedinkel
.
‘-”““’
“
~.fda%iaam~
uSeofc#mbeuyjnioe
wouIdbethe
03&wyof&f&@~s)~ Z$wabarg~~SarwqGLaad_ti~
todnslytrauep”Mdidee?laoffdanduriasryErC’&rf&j
thejuiceresponsiik fmtheobsewd irrhibiti~w&&of
&fe&o%Weha
veevidencethatth isdoes~. FfRm
fkmdthstthe factor(slresponsiblefor the khilition of adherenoe am Aativdy atsble since the inhiitory ati”vi@ of the
~isatill
-.
cOGkOlstesfrompstkats withsymptO@tktninary
trsd&f*
of WV@ dursk J. utions or qqnpmmstk bsa.eriuris
12% 16S,1979.
S.M,XJ.ti~aMdGRd~.kWsw
ofsdheMoeto@beIisloWabyf
ks14Ykolmdarlnal
ypatb.
w=-ti
ISGtw1982”
r’u~dK!wlCxof
4. of&Ly&4LalnfShSr0r&
Edur$d& co&frcsblgacusted
btbeuriaeoipsckIltswitlJ
--bfakas
sndof&&es aubalbdfioraiakued
evidentafl
l?ralwtrmd alltarnetith
E.cdi.
it wss fad thatafteringestion of cranberry codt-
t4theurineofmioe sndhumsnsubjectswas ablem Mcantlyinhibita@rence of E aoli U uroepithelislcells.it thus
G
tit W *
fictor(s) h the *l@=m ~g . t&
qrkfnfku&mur&34:7(U319SL
nomslmetaboucd egradativeprmsse$
mouse
and scurrntdatiin the uriirqorakernaiivdy, a metabolic
Wuct
of cranberry metabolism might aqmnuletein the
urinerh&srdto the&tte.rpodmy.
Urinsryexcretionof
-~dkknreported
ofcrmkrriesandcran~fi~~t
.MiUrenaof&rdJdd&
s.0f61GLMirehnq
D.arKI_N_
CGtitohu
msnanaco
sa!cellsmedistedbymsnmse-rlxqtor%
W
26S: m
x977.
6. SoboW&EYYeuofaubId
-
best*
I
ontumorinductknand
. rwn+&n& hfkfobio&29:
RNAsYntheAs3nAm&&?wm
tokreaseti
the~estioa
kwas foundin &p K?Sent
*
*
hippurk add in concentrations repmxl * aocamt@eintheuxinedidntiWkh~a~
Wmehsve beenseverd reportaintlM~
ontbe
totrwttnfxuuy
titiue
Smeeafd uaeofcrderryjtrke
-The most comptwhensiveinvestigdon was undertieuby PmdromoEsrldassoC@&‘mirstU@indudedu
.fbmsks and16znek
.**perdq
l%epatienta werepHon
for Zl*Th@-two
16-of
dewed a
=MW~~
K ‘rnmh~ti~
16
w270fthe44*@-3*G*&
~Basedonthe
eWencepresenti ti&tid
_
tbdleposidvedinksllwaztaachkvodflle~
am*xWlatedtothe-d*
Cmnbeqyjuketo
pl’e=tadkenoahl~
PdrWnoe~o&elWedtbat
WftMrnwaloftbejakeresultedh romnwoe ofinfecd(m in 62
percentoftbecme& Tflkwoaldbe exp@ed M*
actlngtoblockdbemnce andthuexdo~b
P *=U
oontinuellypresentortlnti*gx)d*m~d
tbebodyoOald&ninstethepatho#p
ll#potentMusedm~*hf&~tof
-Mdons
mkhtbermtkuw?wvlx~~
mm3@nKnt
ofpstkntaWho,slffermcument
ispmsmdyaconsensus
thateradication of the infixtion fo[mbbtxerrnprophylsetic
therepyw(x$d
be beueficid”
However,hXl@ermp~*
with antirnit!mbii a@?ntsfmeents severalproblemsincludingtoxkity, side effzm and the
emergerAQ
ofsedstantpopulatio~ In contr@ Prodrwmosand
assocW#fwdcra.nberryww&Wa_
~
pstknte andnocliicaf sideeffect$svere~
k
~*jui% or the factor(s) tithe jui~ m-tit &
[email protected]~
of value as an adjurrcdvetherapy end pmpbykxk in patients @ =;%$ran~juioein
a
268:57,1963.
I ‘“--:=”
Wkb ~n~
_
ma [email protected]~,
_@$
wb~ pm- ,19g~~~w
-~~
y “~~~”fl~~~-a-~~~,
d.~a~:.P~@f@~.”..
”~
viewlong-term
drugtreatment has proven unsatisfatiry. The
observation that cranberryjuice alau inhibits bacterial adhertObud cells suggeststhat the juice, or the a~”ve factor
“
Of rwurre~t
urina&
‘traei in fedions
in women: a compam~w
~ippurate. J.
trial between nit.rofurantoin and medtenamine
Urol”
126:71,
198I.
/
1
.
~qduction of Bactetiuria ahd Pywia . -
After Ingestionof
CrahberryJuice
..
.
Jfw@wpwarkfdormM
mwefryu-mwJ.tim
fiw~.
Objeofk+To
ageonbadelwa
.kds
.
ofambe17y@ce
:. ...
.
.
fxwx- Supposdsalatqwactondlkuytact
inf’’n#lo
adeqaa@ya?ntdc@an-
●vahtingits
-----~~=-~(-w-wm.
“ ~f!?yefltim—sut@dswwe—a
●
.
AU@44A0
ddemune
. the dfedofregdarhfake
antlrMJrlakaeMe& wlmfa
--
sdwb~
bwwti-ti-
3oomLperday
dinid utility
bipmven&-
Stdiesoftbeeactofc ranbmyjuke
cmme!ddy~~-mgeora-~
--mm=
mostiy
on Cliniealauifuuytlacthkfioas
~~~e.~~~
bwe been unoontmll~ havebeencondncCo@entbut bCkedaanbeayamtent.
ductedonassnakal~and
keyielded
OWxmeM ~-Akx3kw@wsaqkMsixdeaw#kkMSudywifw
confktingresufk=
(h@udywasdequantilaSSf@= W@Q Coaededalql$x?3F’lTM@y
wnOIICfl
MII&@S and tested
Signed tc.+dmss thkquestion.
fwyforbackxwaand
fhefm?Sen@ofwMtetJoocf&
B@erlmaiseoalmoa
amongekkliy
[email protected]@s G3ndom&edto
cheUanbWybevefage hadOddsofbadetluda(deUnedasOQankms.hlnnHngaW%nL)#VWpyudathatweR?onfy42'% Althoughlrxld lktdlriaintbisage
doesnotre-P
is -UdCd
offfW)&S~ttwcontrd~(Fk.Q04).Tlk)djsofre@ingbadd&+ytn@
inUwpnwiousmonhwereonfy27%ofthe
giwnMtheywere&ddw@y&
o&iinthe.confJd group(F=.oo6).
f@acfus?oas.-?hese f-suggestlhawseofacrantwybeverage
uw@qUenC@badeffLJfkwlp yurlaznOwwwwll PrW3km txxikabou(uw
t3fk@SC#Cr@437yjub30n
Cfwur WryWtdtnwhawmkx@?0l0&kM&40n.
-.
FUR DECADES cmnbenydaived
hvqhvekenfhoaghttobeuse“IkUnreddngbactdd infectionsofthe
Nlldder.lmt contlvvemyexktsas to”
Whetberdlisbeliefhas &skins&
eatf!k &c&In 191+ B~%%~
poitedtbatemakles
rkhMellzak*whkhiWcUWedas
-dh&*=dksti
Mote recently, data have been jk+
Sented on a diffkrent potentialmecbadsmofactiom theinMWonbycran-
%erujadceofb
actaiddwenceto
mueosdsu&lces sobota$8ndsdddt
=Mobota%mmda2Mt&tbothaanbemyjdoeadt headnepmducedby
qlil’etmatznen<na largepn3p@orlof
womenolderthan65 yeas will expedintection
ence at &one uxfnaryperyear. ~thfspatkntgroup
pre-
selltsan opportwdfJ tokalnwhether
thengdaxingestion ofaanbenyjuke
beverage anintknce thednaryfiofa
Orthehost%granuloc yterespowtok
.
.
MErHoDs
Afterapproval
byinstitotiona!
review
W-w-eatia
~mamkvdltnlg-tenna reihdlity
GxCheekkdy(tbeEebrewRdnbmtiOtlhterfdrAged)#swendmmfne
p-llw&&=ypg”~h
.
whOvMwapawofgfvingbfOrmedOxk :
$eat%wrehi
tedtopddpateinthe
.
Ctdyifthgywemwmgtobgestatkast
lYxhLOfembeizyjcdceCOCktdlperCk
=tim-tiy.
e%dldmftheyhd
fitl~coti’k
cqandfheotber WmbaaI.dwaseor Uvem demelltf%
dherenm aM&yflM&nlaa&
alineas
&ldieslulwyklded CodGdngresdts
~~m”
Ited
toamcodef!fkorlelras
Xnolatoroanyfhdtjaf
Wasumdidydlepolymdcaunpoand
tbatMdbftedeeltafnadbedns9sso&@d
with
ddnsofEcofiOfeket
isolate &Is compound
tlomaanbenyandbluebemyjuiqbut
notiknll~o
langqguav’q
wmgo, and ● eapplejafees ‘l’heyhyatlLPo=eofwthwens
tothkcompoundineltherthegutorthe
Mad&rp!udwes a bactedostatk el%ct
by blldbidngSpecuk adhesfas present
Onthepitiofthe bactddswfixe.
Despitetheseintriguingiiigs
nnd
the widespread use of cmnbemy bew-
Jll&Wawl WemstadiecLIlldldte%
Neligiblesabjects igreedtopdck
nteandomttibatd atleastoaemine
wqkfterkseline
testin Apia*
m
’40T
Coubf.ningno &
was d+
(Oceanspraycmnbed%w
dWilk# MISS)that wed OWO*
ndoofortosimuMet he@$@d*
earaaceofcouunemidysele.~jdee
cmkWBeaaseduM@
]lemneeis commonamongW*
‘Otllem
both
the cranbem’
ev&&w&&ee@rd
n. Eewrages weN
:tkdc0fbirtef3weptfo
and Pb~
Wi$h-k@@&liYet@&
mded
-
mP-
Iotnum- ““ ‘--:”:.-,:{:. -.
...
---
“
k
en
la
bn
~
mwemDend&edtoconsmne
thebev-
‘%!x$%giye~~af
intheaa@ct?sin
frumfaerstudyalmo
nthdter
.
bied
as
xl
goi@asto@-w-Yw&
Cr- 311Y=-uwmwPmzlot&*
cowiiwm-~etkllmrm
vt&the4he~
Snentoffdwkhw-sq,+%
gsg .
ta-vdwereesdn@ed $epqe&&
alajedshathecr’anky
oddvseveidigits
etftdodidaltuicationmlmberti.e
mmbertodetendnewhl&
coded
f%- number beverage woddbeased
~*[email protected]==norksigatora
Wete aware of
of
pente
-8@W12mbject-re
ceWg
~
tieq%
al’placebobever*-mtiwnotti&*
eameaycmlkzyproduetso therthan
thoeedMdl@ed tothemdnring the
~.
1%pnwent the poasiiili~ that
thcendofayantibiotkcoam%
= alndaniddyd+&acdtnrt%
senaitwlty
Waw
end
pezfomledoneacburinesampkiuunt%.
Coliectim
diatety
antwtie
after
testing
v
‘id
.ptia~wfor TepIi-
ties(_%@oaIId
U* sampkefathetzansitions
Wcollected until each subject had
colItriiu!dsbasehne qecbnenphssk
monthly Spe&ens or hed yW’uil&WJ
ti~ the dy. mti
%
all *
samples confafbu
by subjeets whoPrm4dedat bat one sample
-%2!
~~assoclatedvvith~.
mentassigmne!kmewdtofaualysk~
theee logistic modelswas the l-month
study fntewal.FirsQwe consldemed
inte!vak WMoutbacteriuriaphs pJwfa
at the beginningofthe inbsrvalandpre.
dktedtheprobabiBtyofbxteriuAaw”th
pJ@aattheendofthe
intervaLAeecond modelevaluatedintivdtb
bacxnl@tfnadvertent&consumestandard monthlycolkctions.%npks ofboth tbe
t.exhdaandpyuriaat the begidngand
predicted the probabfity of no bacteribhqeekewhemin
tbein- ~~
placebobeverages ~
dft@io&+all sach beveragew con- ana&ed by Wan Sbarq PhD,Weiz- uria plus pyutfa at the end ofthemonth.
Wtcd to the placeboproduct @lrough- mann
ImX&l@
Rehovo&Isrd#foftheir
REsuUt’Soat the institutiondtuingthe study. To
apdty to Mibit.adhsion byE cd to
ensure that each subjeet continued to
AtotaIof618 urine spdmenswere
h-~,
= d=~
r
re@ve the ~
beverag~ patients
vioudy.@’fJ
Ike sampleswereidenti- Colkctedtitnthe staldysab’’after
werw interviewed monthly. In additkxq
fied by code number only to ensure
basdine About one W
@wed
aIfbOttlecapewere colkctedfi-ornp
blindedassessment.
pwwthoflO$ol@lkmsper!nUiMeror
ficlpants each znon~ and tie coded lot
AsecondmsearthassktanGawmre
more,about one third producedno bacammberprin
tedoneachbottle capwas of*
Aialgm@and theremdnderyidded
~~
*9
or =M*
asdentered data into a rekntennedkte gmvth of oqpudsm J3smeeM@db YaresaVAassknL
size CalcaMotla Wpertioneld*The
ptfrnagoutcome
%etW&zc
ofiwasthe mostcomtnon.
befbrwthe study began We aswas bacterM9 (organkm numtdng
denti6edorgankm(43%ofkolat&l ~
ald&
regeldlem Oforgdsm) with
solnedtbattbe ovemltzate of bacteriWbsieflathesecondmostcommonsingle
cniaandminthecontrvlgroapwould
“ b’lagivenstudymonth. asub-G%%*4
floIaWcoont@for
beabouta60,endtbatthe@lctiona6
urine
P whocontinuedto con:hd’W*~~
wnpks wem includedin the an?$sk
*of
Weasedkgistfcregrdon emdyskto
@knhti-,=*p*
wolddbe40%#
f3sok@reptesented by BcoH=
!dimetetbeoddsthatthisoatcomewas
‘
themteinthe
Wciatedwithdgmnenttothecmn*-M-M-=
“ w y~
~ydw--~~
Ifectioniny
Womea
lerlybeveragegKutp.Eaehp@kipant
r
=
followIndadedata
!ontdbuteduptoskesWsm@softhle
wOuld_asampIe
akeof92
= analyses
ftlew!bgzW,
atot410fl$2
oman153$tlbjectswho@@xltedone
toaixWmv=ap
wetW2dled K tllea@@ata
te
=ee~
‘Motwwineumpkeafterlzndond=
s
awpresen@oa
tbe163eabJxiewho
mmtbesamepMMpalltWetWlotstatql~ti~~d~
abaseheuziuesmpleandat
MWly
&end44WeW’esMenteofllong~
%SWfromthekE%% adwonalsxmpleaftermdomrefilcIIi@@@hosezzndomW
istk
llmodelthattreated as“fz9tkZ?odatawemavallableforsab
ssmentsesbKkpendentWmm@xs@
ecranbenygrOap end610fthOSeti
thestudywf#eplacebo grwpeompktedti
W6
ytheesdmdlgquadolla ppluachof
any lnizteSampksafter
mths of study. As sbovmin Tabk Z
*~
*.U
Logisticregvesdozl
the
thgluupswereshnikrh %%nmk
Iodelswfthtldjustedawereusedto
I -At study%itry,a geMric nurseobMedkatlonstlsedtand~~*of~camineandacljastfoithe efkctof bactaineda complete*
history and
‘ pmbkmq as well as bactesiti
riuria with pyuria at baseline when
hstmsedsubjectsintbepmpermethod
Camining
tile effectof cranky bevuz@andltrinaq tradsW@m*
ofobtabdw a mldstmmm. cfe.an-voided
w!inq Wtough subjects mdomked
w Onstady outcomesafter randomto the cranbeny group had a lower=te
t!dh%an ad&@ite
Ckiil-voided spedered io the regresdon model was hisxWiotxuAna@=tM*~w
men themsehf* thegerktaic nurse as- toryofudnary taactinkctkninthe6
y. tily f- subjects wed ~
ddedhl pdOIYnh&tied~atiDm
and X2 months beforethe sdY.
[LwMuxwmmuuLKWn
ktchgiwwl.
-
752
S12bjeCtSitit.he
ill$titUtiO!d
settlngwho
efterthe baselinecolkctiok whet.heror
We!t ?9ndOmized to
not they -bed
~
~(ch
plecebo
bev-
9. lS94-Vd
271. No. 10
enrokd fw ill six
6aat7tia and Py@ NW Cranbeny@ce
@e4cx+Awm
.. -,
e( a{
.
.
~.
-.. .
.
.
Tan&ma
L%lmethwbpw
uinuy~
.
618dd0C-
~
u8d-
COzle&&tkecranbenyglwp#@)
4(SJ
tS@2j
0
2(23
Ym
du3iaor3JYu& oftbe4ndnes2111nl&
. ,.,
*1
2(3J
11(laj
(4%) had bacterfulfa and pyuda mm
X’entw”ththazlb’’
1(q
.
3(+
tmct symptims,
“
sqortinglufnazy
Compad w-th37(7%)
of496wine smlpk?sin thepfzcebogmup,
-=thkdid3aotl-eaastaMc2Jaig-
~m
&tibioticuse Sfh?rmldonlkadotlinduded 16kIst9nces oftmstnwntforurj-
ended
test fm
kukoqte eztaase
pyuri2@4%0f21S
*6af@5hthe.
U)[email protected]@3Srs&raMetot&enrj. contmlmauvs 29%inthecranberry
rytlact werenoted onzz.o%ofd
merencewas not stimqo. h t.kk
nonthintervdhktodesconsunl~a
tkticdy si@6c2nt intherepliate
2s-.
tpmtmed
kspaandsubjectmptexoeeded
)% Ofsadgnedqwntitk?s
iudy&eragean3e2sud
Iac&lWawfthpyuriawasfdin
.%ofm3ne#331ples fntbepJaczbo
ap233do&150%k3theg3uuprand2edtotbeuan?xmy beversguWe
~
.
nauytractinfe+nfn tbe controlgroup
WWloopemon-montbs)va eightinfstances in the experbntal gmop (L7
perlo6 ~n~>adam
to
ase antibiotics were made by mbjectd
own Jdlysicsaq who V?emmm
of
thestlldydesignorg
roupssd
t.
No sigdknt differencewas of%?
3ntheacW&ationofurfne Inthe-d
$dyaia (P=.09).
-mupwpti
m average
l-3yO@l
pbabili~of PH=6.0
ands.6,-v*
.
..
(hedian.
“
-’?.
lll-oftbeeodedml@ bev&
ages&tieffei#033 kac&rk!sdll+
&~co33dacted byf)z’sbalwld
Chan@hrn
w2s34intke
Colkaguesatthe wd2m2n33133stitu@
n
l-m033thpmbaw@fCban@rp330n-of J2s2mp?e20f theactfvect2nbeny
fix3nddf&m3Cek3ti3en3eanppblfected
to
beveragetlsed~tbestadywere folmd
b33.ofkMwfq@C
m3tke-ydYhlE
pksk3e2dgm@&rasf3k3&%
-=w”~aatiati~
.
%vsw%#mspeCt&61y$
mledit- &3dk133 toSl&lX3tidaoam
iisi!!ii!!?i”iyiil!ii%iii?
yasmotpr
esenwkerlrst
p’&@a’+&
CqiwN’r=
Wa=ti_mh&
tkancontrokto
%36
Deqite &C2des
.#si?i5i5s!iii55!!q
hel’k?kl’k?k w
wnteld3begMgVaabadenum
assesmats Owle
%dMdUsk vrr&aad9.amd9nR&f m&&tieoRfmgti
orhcterM2
.
.adomked to the emnbeny bevdatfve
M-an
to eoatm[ subjects(9S%
t0a7~P=~.
rsCtpel-skWwhenwe2d
ddtQ
W a -[e
desaibii a bk-
zfmbpyark sarnpfeat the end of the
fnterrali33thecmnbeny gmopw027
v=wqindidngthatt
faeaesubjects
Weleonly sboutaqualterxwy=
271. No. 10
:
Cem&3gtheef&t20f
thet3rhuuytri@toour
stJ2dy
npments
tm~
ktedud2with
atkktduria r eldexiywocnenkcoti
nxdy Ok~
itdoes not represent9
conditionwithanegativepgnosk?or
me thatl%qulll?streatment.- Howfutinaty@ctin&cthinh6
Wer,demmstmtionof the “cap2ciQof
3 prior to ran$xqhtion (ORfor
xan~beverage
toreducetioxllrm ill Crsnbemygluap, ()~
(O~03~JkllZJor123nonfhs (0~0~,
W3ceofbaeMHaWithpymfab3
elderly
) or Wmonths@or tomndom- P=.(ll)bdm t@tudybegardfostsubmmendoe
slendcre dencetothebelkf
(OILO@kOllSubjectsin the Jxts * bacteriuria were 22Yln31ton3- hatficontakisa substancewithbielogic
ciitityill rewontothe~V IWW *
~~iti
a trend ‘ ‘*and manywithsymptofnz
&f&ble
less lXXt&M2 ke2pt@jve of to the orimy tmct did not have bacteYe efkt was notseen-m’the-f%ststudy
arcit 9. 1994-Vd
.
:
.
.
tocontinuetohaveabac@iurkp~”cwines2n@~3hese @3ing2wem
afsoadkcted byadjustingforahktory
ofurhuuytractinfectimin
thetjmonths
controls
f3adetiad
P@t A@~Juice
(ngesliiwxne(a(
.
. ..... .-
753
.
.
.-
.
.
.
$=fJG~#*-4t08weda
mtimww”~ti
Ofuseofcmberly bevemgedthell
Iiearlyidentic dx?tesofback?dud
aand
P@==dd)out
the=mekvet!tlds
JT@=tb=-ld--=&aecou&ecouldbecompatMewithmo& coaMleMrInakpkateasewnen
@
ficafkaofglIt~whkhaletbef#picJd
coatmkabjec% wew awe fik+ to have
MstoAsofu.xinq
tnctinC~33e
I@ho@na inu.dnmtr actlnfwtkfs
.
effectofihemnlMlzybep3g&pU-&&
eveawheatH2Mbnatmn
fn the rnuitivaxiate xegresdon equation.
di%km!lalightfyb
. l%e rate ofti-tion
totm2tarhxuy t7actinfodion2ufg@2
thatthisdiik-ence Jaayhawaanif”
It2elffaimportantclinical outcomes
fxwellthewg
luupsofthosewhoconiribu@d one ar more tuiae sampka [01--
Ye&dnot@devidence
thaturimuy
a@ka60n
was responsible for the obsezvedeffd#ince themedianpEoftaine
a2mpksin thecraabenygmup (6.0)w2s
actwdly Mgherthamthath the@Xpe!imentalgroup #.6). While cmabenyjuke
h22beenadvocateda2 am@wyacM@X
to plvvent udnaly *et irlfnot
all stadies have shown a zeduction in
urbwpHwith
mnkny juiceh&StiOq
eves with con2um@ionof2000mLper
t6!l@%)
--~
of’722djectsrnthecranbenygx9upfmapktedaU6monthsoft
hestudy compred
Withdl(zl%) ofuintheplacebogroup.
If2@jectswith2tdieudnea2mpkwere
more iikdy to drop out berm oJntrimutiagthefb116months ofstudy, thkcould
havebdkncedourfm
din
a#oughswch
[email protected] &
Dea#ethe popuHyof&ofcran-
~
j~
for PreventIonof minary
-inf.ectioqthepm&bilitiA4nndw.wl’heamounta usedinthistdd
@OOxaL)maynothavebeenlargeenoughldtion 2naly2esiadhte * its effect
in
to jxudueethk effeik Bla_I
Wa2mom pllxlotmced in eonwdlg
*
samplesout of a 2t2teof batteduziawftb fi22comp2redm”thpreVenting& convemionof aoninfectd
uiine#mpk2tib9ct4Aul%pyWcone.s
“ WMe this does not implythatsucha
-m
shoold&place mtfbiotica~
z2Kl$=TL-&’
wasuot@ated toaainepHor Mpurk
Sddhlnatkmbut!zth$
!rtosomeLctedosta$epmpeltkof
cmnbenyjtdeeor
its amponenk
.
.
~.
%Bktbtkk NIL Tkspdesw&offdsh
rehtbntoctiaoiqdtbn ofthear&RA’ck/Uam #d 1914$&#94so.
zMoall)v.GbHuoIlsoa tk@T&encssof
.e&Jxr#&inww&&iaUwdL
.
.
.
1
msanl-lm.
2&!iz-w-
.
SJxJmlcydB,BbunclLf
EUkdofa7abary&dc’e IL Ofak & Goldw+frhi’4ti’usAsyzr.R
[email protected]
R4xlw9g&s7-2$2
[email protected]
bkaddinadd@blgtbearbwllImd.#Jlec&?nxk-.—.lz PapasPwkuadlcA_mA_~Gc
-J~fkdbNUrdwlsw
lm.la!l
—. .—
jukktbcuwlaalt
$. FdlU@IZ,Re&IOIIBGPSIIM
EALIIUCff@
Sourbd Mc$.19Gwm20.
dnlgs&uroA*!190w&
@f~aluhn’addii
aod1400ddklli
reaewe.JMdk. 1933f4s43.
6. NkkeYicEuzinepKxlYdofprcsUnA*
U.ZbarHB.NewraWbadcAd
IO13fdinkuOiuMed C@ttwk
Uleusofcmbtqj dccandmscwbkadd.ti
P&# Md R&b. 1975565M.
Z McbodllcNatuiaMCMetIWUM@
QMtKmdduiitkmdtkdkxdb%g$
*
Ad&@%onm
19?8ss.s54
& s9boUAElnMbi(ionefb4c&Mm$kmccby
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