Abst ract
Submitted: May 23, 2016 0RGL¿FDWLRQ-XO\ Accepted: August 22, 2016
Role of 1% alendr onat e gel as
adj unct t o m echanical t herapy in t he
t r eat m ent of chr onic per iodont it is
am ong sm oker s
Obj ect ive: Alendr onat e ( ALN) inhibit s ost eoclast ic bone r esor pt ion and t r igger s ost eost im ulat ive pr oper t ies bot h in vivo and in vit r o, as show n by
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ALN gel as local dr ug deliver y ( LDD) in adj unct t o scaling and r oot planing ( SRP) for t he t reat m ent of chronic periodont it is am ong sm okers. Mat erial and Met hods: 75 int rabony defect s w er e t r eat ed in 46 m ale sm oker s eit her w it h 1% ALN gel or placebo gel. ALN gel was prepared by adding ALN int o
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plaque index, pr obing dept h ( PD) , and per iodont al at t achm ent level ( PAL) ] w er e r ecor ded at baseline, at 2 m ont hs, and at 6 m ont hs, w hile radiographic
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and at 6 m ont hs was calculat ed on st andar dized radiographs by using t he im age analysis soft war e. Result s: Mean PD r educt ion and m ean PAL gain w er e found t o be gr eat er in t he ALN gr oup t han in t he placebo gr oup, bot h
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sm oker s. Thus, 1% ALN, along w it h SRP, is effect ive in t he t r eat m ent of chr onic per iodont it is in sm oker s.
Ke y w or ds: Alendr onat e. Chr onic per iodont it is. Sm oking. Regenerat ion.
Anuj SHARMA1
Achala RAMAN1
Avani Raju PRADEEP2
http://dx.doi.org/10.1590/1678-7757-2016-0201
1Dental Pearl, Jharkhand, India.
2Government Dental College and Research Institute, Department of Periodontics, Bangalore,
Karnataka, India.
I nt r oduct ion
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m ain aet iological fact or s in per iodont al diseases10.
Addit ionally, ex t ensive r esear ches suggest t hat host -derived enzym es, cyt okines, and ot her m ediat ors play a dir ect r ole in ex t racellular m at r ix ( ECM) dest r uct ion in per iodon t it is2 0.Th e bact er ia, t h er ef or e, in it iat e
disease by act iv at in g h ost m ech an ism s t h at t h en dest roy t he support ing st ruct ures of t he periodont ium . Th i s j u st i f i es h o w i n i t i a t i o n a n d p r o g r essi o n o f per iodont al diseases can be inhibit ed by int er fer ing w it h host fact or s.
Convent ionally, periodont al disease is t reat ed by m echanical per iodont al t herapy, but cer t ain cases m ay require adj unct ive chem ical periodont al t herapy. Chem ical per iodont al t herapy m ay inv olv e var ious h ost m odu lat or s f or con t r ollin g per iodon t al t issu e dest ruct ion.
Bisp h osp h on at es ( BPs) ar e car b on - su b st it u t ed py r ophosphat e ( P- C- P) analogs t hat include pot ent i n h i b i t o r s o f b o n e r eso r p t i o n , w h i ch h av e b een effect ively used t o cont rol ost eolysis or reduce bone loss in Paget ’s disease, m et ast at ic bon e disease, hypercalcem ia of m alignancy1,and ost eoporosis16.
A l e n d r o n a t e s o d i u m ( A L N ) i s a n a m i n o bisphosphonat e and, once t aken up by bone, it act s as an ant iost eolyt ic agent . ALN binds t o resorpt ion
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associat ed wit h ost eoclast ic act ivit y. This release leads t o a rise in t he local concent rat ion of ALN, result ing in an alt er at ion in t h e r u f f led b or d er m em b r an e charact er ist ic of ost eoclast s w it hout dest r oy ing t he cells. Therefore, ALN seem s t o have a pot ent ial t o be used as an inhibit or of alveolar bone resorpt ion in t he t reat m ent of periodont it is.
Previous st udies have shown t he effect s of syst em ic ALN in hum anand ot her anim al m odels in decr easing bone loss and incr easing alveolar bone densit y12,15,17.
Ad d i t i o n al l y, st u d i es h av e o b ser v ed t h at t o p i cal applicat ion of ALN was highly effect ive in r educing
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sur ger y3,4,22,24,30.
Ev idence fr om cr oss- sect ional and case- cont r ol st u d ies in v ar iou s p op u lat ion s an d an ab u n d an t num ber of r ev iew s on t he subj ect have show n t hat adult sm oker s ar e about t w o t o four t im es m or e likely t o h av e p er iod on t it is t h an n on sm ok er s. Pr ev iou s st udies indicat ed t hat sm okers did not respond t o
non-sur gical per iodont al t herapy2,13. Addit ionally, sm oker s
show ed less pr obing dept h r educt ion and at t achm ent g ai n , co m p ar ed t o n o n sm o k er s, f o r p er i o d o n t al sur gical t r eat m ent11,23.
Considering t he abovem ent ioned fact s, t he current
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gel as local dr ug deliver y along w it h scaling and r oot planing ( SRP) for t he t r eat m ent of int rabony defect s am ong sm oker s w it h chr onic per iodont it is.
Mat er ial and m et hods
Sour ce of dat a
I n t his 6 m ont h follow- up longit udinal int ervent ional st udy, a t ot al of 52 m ale sm oker s ( age range: 30- 50 y ear s old) w it h chr onic per iodont it is w as select ed fr om t he out pat ient sect ion of t he Depar t m ent of Per iodont ics, Gover nm ent Dent al College & Resear ch I n st it u t e, Ban g alor e. Th e r esear ch p r ot ocol w as pr esent ed t o t he Et hical Com m it t ee and Review Boar d of t he inst it ut ion. Aft er et hical appr oval, all subj ect s w er e ver bally infor m ed and w r it t en infor m ed consent was t aken for par t icipat ion in t he r esear ch. The st udy was conduct ed fr om Mar ch 2010 t o Apr il 2011.
Select ion cr it er ia
Sy st em ically healt hy subj ect s w it h pr obing dept h
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m m w it h no hist or y of per iodont al t herapy or use of ant ibiot ics in t he pr eceding 6 m ont hs w er e included in t he st udy. Sm ok ing hist or y was collect ed by self-r epoself-r t aft eself-r a st andaself-r dized quest ionnaiself-r e. Subj ect s
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cr it er ia est ablished by t he Cent er s for Disease Cont r ol
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use of sm okeless t obacco in any for m ; alcoholism ;
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46 subj ect s ( out of 52 enr olled) , w ho m at ched clinical and radiographic param et er s, w er e r ecr uit ed for double- blind clinical st udy ( Figure 1) . Mult iple sit es fr om t he sam e pat ient s w er e also consider ed in case
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random ly ( by com put er generat ed syst em ) assigned t o eit her ALN or placebo gr oup. 37 sit es ( 2 failed) and 38 sit es ( 4 failed) com plet ed t he st udy in t he ALN gr oup and placebo group, respect ively. Anot her clinician ( AS) t r eat ed subj ect s enr olled t o eit her gr oup. All pr e- and post t r eat m ent clinical param et er s w er e r ecor ded by an ex am iner ( ARP) w ho was m asked t o t he t y pe of t r eat m ent r eceived by t he subj ect s, w hile anot her clinician ( AS) pr ov ided t r eat m ent t o bot h gr oups.
I n t he ALN gr oup, sit es w er e t r eat ed w it h SRP followed by 1% ALN gel ( 10 m g/ m l) local drug delivery, w hile in t he placebo group sit es w ere t reat ed w it h SRP follow ed by placebo gel placem ent . Subj ect s w er e blinded for allocat ion int o ALN or placebo gr oup. SRP was per for m ed at baseline unt il t he r oot sur face was considered sm oot h and clean by t he operat or ( AS) . No
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a f t e r t r e a t m e n t . Cl i n i ca l p a r a m e t e r s, i n cl u d i n g
PRGL¿HGVXOFXVEOHHGLQJLQGH[P6%,18, full m out h DQGVLWHVSHFL¿FSODTXHVFRUH3,28, PD, and PAL, were
r ecor ded at baseline ( befor e t he SRP) and at 2 and 6 m ont hs. A cust om - m ade acr y lic st ent and a no. 15 color- coded Univer sit y of Nor t h Car olina per iodont al pr obe w er e used t o st andar dize t he m easur em ent of clinical param et er s.
I nt ra- exam iner calibrat ion
30 sit es w er e ex am ined t w ice for int ra- ex am iner c a l i b r a t i o n . Ca l i b r a t i o n s w e r e c o n s i d e r e d f o r m easur em ent s sim ilar t o 1 m m at t he 95% level.
Radiographic assessm ent of I nt rabony Defect s
( I BD)
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using an im age analy zer ( Scion im age Cor porat ion, Fr ed er ick , MA, USA) . I BD w as m easu r ed on t h e radiograph by m easuring t he vert ical dist ance from t he cr est of t he alveolar bone t o t he base of t he defect . I ndividually cust om ized bit e blocks and a parallel- angle
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as p ossib le. All r ad iog r ap h s w er e r ev iew ed in a single r efer ence cent er by a m asked evaluat or. For assessm ent , radiographs w er e scanned w it h a 6400
DPI scan n er ( Ep son Per f ect ion V7 0 0 , Ban g alor e, I ndia) by an evaluat or w ho was blinded t o t he sur gical procedure perform ed in t he subj ect s. The radiographic I BD dept h was m easur ed by com put er aided soft war e pr ogram , as pr ev iously used25.
Pr im ar y and secondar y out com e m easur es
The pr im ar y out com e of t he st udy was PD and PAL. The secondary out com es included com plet e bone
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For m ulat ion of 1% ALN gel
ALN gel was pr epar ed as descr ibed by Reddy, et
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Guj arat , I ndia) was dissolved in a r equir ed am ount of dist illed wat er t o achieve 1% ALN concent rat ion. A w eighed quant it y of car bopol 934P ( 2% w / w ) was t aken and added t o t he dist illed wat er. The m ix t ur e was gradually st irred and carbopol was allowed t o soak for 2 h. 1% t r iet hanolam ine was added t o neut ralize t he car bopol solut ion and t o for m t he gel. The pH was adj ust ed t o 6.8. Finally, t he r equir ed am ount of m et hy lparaben ( 0.1% ) and pr opy lparaben ( 0.05% ) w er e dissolved in et hanol and added t o t he gel. The placebo gel w as pr epar ed by t he abov em ent ioned pr ocedur e w it hout adding t he act ive ingr edient ( ALN) .
Local dr ug deliver y
The pr epar ed ALN gel ( 10 m g/ m l) was dispensed int o t he per iodont al pocket s w it h int rabony defect s using a sy r inge w it h a blunt cannula. Pat ient s w er e inst r uct ed not t o use for ceful br ushing or int er dent al aids at t he t r eat ed sit es unt il t he appoint m ent aft er 2 m ont hs and t o avoid chew ing st ick y or har d food.
St at ist ical analysis
Pow er analysis calculat ions w ere perform ed before t he st udy was init iat ed. To achieve 90% pow er and det ect m ean differ ences of t he clinical param et er s bet ween groups, 30 sit es in each group were required. Th e ca t e g o r i ca l v a r i a b l e ( si t e - sp e ci f i c PI ) w a s ex pr essed as per cent age and t he cont inuous var iable ( Full m out h PI , m SBI , PD, PAL, and I BD dept h) , as
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w as per f or m ed w it h SPSS v er sion 1 5 , SPSS I n c., Chicago, I L, USA.
Result s
4 6 su b j ect s ( m u lt ip le sit es/ su b j ect ) ou t of 5 2 com plet ed t he st udy ( Figur e 1) . All subj ect s t olerat ed t he dr ug w ell w it hout any com plicat ions or adver se react ions. Soft t issues healed wit hin norm al lim it s, and
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Parameters (mm)
Visits ALN Placebo t-value† p-value
Probing depth Baseline 2 Month 6 Month
7.84 ±2.04 5.05 ±1.78 3.68 ±1.93
7.62 ±1.97 6.38 ±1.84 5.57±1.88
0.21 9.87 18.253
0.645 <0.002* <0.001* Periodontal
attachment level
Baseline 2 Month 6 Month
6.43 ±1.77 4.05 ±1.94 2.49 ±1.53
6.19 ±1.54 5.22 ±1.73 4.41±1.83
0.4 7.36 23.79
0.531 <0.008* <0.001* Intrabony defect
depth
Baseline 6 Month
5.18 ±1.00 3.07 ±0.94
5.10 ±0.95 4.97 ±0.95
0.123 74.03
0.727 <0.001*
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† t test
Table 1- Probing depth, periodontal attachment level, and intrabony defect depth in alendronate and placebo groups at different time
interval
Figure 1-6WXG\ÀRZFKDUW
and full m out h PI scor e, but im pr ovem ent was not
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m ont hs ( Figur e 2) .
I n bot h gr oups, m SBI show ed no differ ence at baseline, at 2 m ont hs, and at 6 m ont hs ( Figur e 2) .
Cl i n i ca l p a r a m e t e r s PD a n d PAL sh o w e d n o differ ence in int er gr oup com par ison at baseline and
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Radiographic param et er I BD show ed st at ist ically
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alen dr on at e gr ou p, in com par ison t o t h e placebo
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6 m ont hs ( Table 2) .
Discussion
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1% ALN gel along w it h SRP for t he t r eat m ent of I BD in sm ok er s w it h chr onic per iodont it is and show ed
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clinical param et er s com par ed t o placebo gel.
ALN an d ot h er in g r ed ien t s of g el f or m u lat ion ar e appr oved by t he Food and Dr ug Adm inist rat ion ( USFDA) f or or al u ses. St u dies2 4 , 2 6 h av e ex plor ed
differ ent pr oper t ies for var ious concent rat ions of ALN and found 1% ALN gel is t he opt im um dosage for LDD, t hus 1% ALN was t he choice for t he cur r ent r esear ch.
ALN is a bisphosphonat e t hat act s as a pot ent in h ib it or of b on e r esor p t ion . I t is n ow g en er ally accept ed t hat t he m ain cell by w hich bisphosphonat es m e d i a t e t h e i r a ct i o n i s t h e o st e o cl a st . Va r i o u s
m echanism s t o be involved ar e inhibit ion of ost eoclast r ecr uit m ent , ost eoclast adhesion, ost eoclast act iv it y, and shor t ening of ost eoclast lifespan ( apopt osis)5.
Sev eral r epor t s hav e show n t hat bisphosphonat es not only induce ost eoblast s t o secr et e inhibit or s of ost eoclast- m ediat ed resorpt ion, but also st im ulat e t he for m at ion of ost eoblast pr ecur sor s and m ineralized nodules, t hereby prom ot ing early ost eoblast ogenesis7.
Hist om et r ic analy ses show ed m or e per cent age of bone in t he fur cat ion ar ea t hat was t r eat ed w it h 1 m L sodium ALN ir r igat ion ( 10- 5 M) , w hen com par ed t o
cont r ol gr oups of ex per im ent al per iodont it is in rat s at 7 and 15 day s3. I m m unohist ochem ical analy ses also
ex pr essed st r onger ost eopr ot eger in im m unolabeling, w eaker r ecept or act ivat or of nuclear fact or- k B ligand im m u n olabelin g, an d few er t ar t r at e- r esist an t acid phosphat ase- posit ive cells in rat s3. Collect ively, t his VWXG\ VKRZHG VLJQV RI VKLIW IURP LQÀDPPDWLRQ WR
per iodont al healt h.
To our k now ledge, t her e hav e been no st udies report ing t he use of 1% ALN gel as LDD in t he t reat m ent of ch r on ic p er iod on t it is in sm ok er s. Th er ef or e, a dir ect com par ison w it h ot her st udies is not possible. Co m p ar i n g ch an g es i n cl i n i cal an d r ad i o g r ap h i c p ar am et er s w i t h 1 % ALN g el as t h e l o cal d r u g deliver y used in t he t r eat m ent of subj ect s w it h CP and aggr essive per iodont it is ( AgP) in pr ev ious st udies26,27,
t he im pr ovem ent in clinical param et er s in t his st udy w as higher in AgP subj ect s but low er in subj ect s
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subj ect s but low er in AgP subj ect s. PD r educt ion was
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as r epor t ed in pr ev ious st udy26,but gr eat er com par ed WR $J3 VXEMHFWV PP DW PRQWKV DV
obser ved in pr ev ious st udy27. Sim ilar ly, PAL gain was ORZHULQ&3VXEMHFWVPP EXW JUHDWHU FRPSDUHG WR $J3 VXEMHFWV
m m ) at 6 m ont hs. Conver sely, per cent age change in
Clinical parameters % change from baseline
ALN group Placebo group t- value† p- value
Mean PD 2 Month 6 Month
2.78 ± 1.20 4.16 ± 1.23
1.24± 0.83 2.05± 0.94
41.01 68.1
<0.001* <0.001* Mean PAL
(mm)
2 Month 6 Month
2.38 ± 0.95 3.95 ± 0.88
0.97 ± 0.92 1.78 ±1.22
41.317 75.789
<0.001* <0.001* Mean IBD (mm) 6 Month 2.10 ± 0.69 0.12 ± 0.04 302.01 <0.001*
%RQHGHIHFW¿OO 6 Month 41.05 ±11.40 2.5 ± 0.93 420.07 <0.001*
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† t test
Table 2- &KDQJH LQ PHDQ SURELQJ GHSWK SHULRGRQWDO DWWDFKPHQW OHYHO DQG LQWUDERQ\ GHIHFW DQG SHUFHQWDJH FKDQJH LQ ERQH ¿OO LQ
ERQH¿OOZDVQHDUO\HTXDOEXWORZHU LQ$J3VXEMHFWVDQGQHDUO\HTXDOEXW JUHDWHULQ&3VXEMHFWV26,27.
The r esult s of our st udy ar e in line w it h pr ev ious st u d ies t h at h av e r ep or t ed t h at ALN w as h ig h ly e f f e ct i v e i n r e d u ci n g a l v e o l a r b o n e r e so r p t i o n
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placebo gr oup at 6 m ont hs. This is in accor dance w it h our pr ev ious st udies26,27. ALN LDD also show ed VLJQL¿FDQW SHUFHQWDJH RI ERQH ¿OO FRPSDUHG WR DWRUYDVWDWLQ /'' LQ D
recent clinical t rial22. Considering t he abovem ent ioned
fact s and result s of previous st udies, it can be proposed t hat dir ect subgingivally placed ALN w ill be a bet t er appr oach for per iodont al healing of bony defect s in sm ok er s w it h ch r on ic p er iod on t it is. Th e p r ob ab le
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can be ex plained by t he fact t hat tobacco com ponent s have show n t o have dir ect effect s on cer t ain bone r esor pt ive m ediat or s. Tappia, et al.29 ( 1995) r epor t ed
t hat sm oker s ex posed t o bact er ial lipopoly sacchar ide
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I L- 6 t han nonsm okers, while ot her st udy report ed t hat abr ogat ion of int er leukin- 6 pr oduct ion by alendr onat e in hum an ost eoblast ic cells can occur, which could also affect ost eoclast ic act iv it y8.
Th i s st u d y h a s co n si d e r e d t h e t e ch n i q u e o f subgingivally deliver ing ALN dir ect ly int o pocket s of sm oker s w it h chr onic per iodont it is as t he local dr ug deliver y sy st em s t hat offer s t he advant ages of high concent rat ions at t he t ar get sit e w it h r educed dosage, few er applicat ions, and high pat ient accept abilit y9.
Com par ed t o a sy st em ic r egim en, local deliver y m ay
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and pat ient com pliance, as also r epor t ed in pr ev ious st udy19,26,27.
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aft er 6 m ont hs fr om baseline, w hile ALN was found
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at 1 m ont h and absent at 2 m ont hs, as r epor t ed in a pr ev ious st udy26. This can be ex plained by t he
release of BPs from bounded bone m ineral during bone resorpt ion by ost eoclast s. This could lead t o a localized accum ulat ion of BPs, w hich could dir ect ly per t ur b ost eoclast ic act iv it y or indir ect ly t ar get ost eoblast s and m acr ophages, r esult ing in decr eased ost eoclast ic chem ot axis and act ivit y6.Carbopol was used as vehicle
for pr epar at ion of ALN gel in t h is st u dy, w h ich is consider ed t o pr ov ide int im at e cont act and pr olong t he r esiding t im e of a dosage for m in t he per iodont al
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com m only r efer r ed as m ucoadhesion, aft er LDD14,21.
Conclusion
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im pr ov em ent in per iodont al clinical param et er s in sm okers wit h chronic periodont it is com pared t o cont rol subj ect s. 1% ALN can be used as a local dr ug deliver y sy st em along w it h SRP for nonsur gical m anagem ent of per iodont it is.
Acknow ledgm ent s
Th e au t h o r s t h an k Ap ex Heal t h car e Li m i t ed , Ankleshwar, Guj arat , I ndia, for providing a gift sam ple of ALN; Depar t m en t of Ph ar m aceu t ics, Al- Am een College of Phar m acy, Bangalor e, I ndia, for helping us pr epar e ALN and placebo gel; and Mr. Jagannat ha PS, for carrying all required st at ist ics. The aut hors declare
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Refer ences
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