nost Modu|at|on

W PosL response modulaLlon lncludlng regulaLlon

of
%|) AA metabo||tes
%||) Lks
%|||) MMs
%|v) bone remode||ng
%v) cytok|ne receptors and
%v|) n|tr|c ox|de synthase %-) act|v|ty
@ree poLenLlal approaces Lo osL modulaLlon
ave been consldered
1) lnlblLlon of maLrlx meLalloproLelnases
(MMs) wlL ant|prote|nases
2) blocklng producLlon of prolnammaLory
cyLoklnes and prosLaglandlns wlL
ant||nammatory drugs and
3) lnlblLlng acLlvaLlon of osLeoclasLs wlL bone
spar|ng agents
Ant|prote|nases
W nLlproLelnases used ln Le LreaLmenL of
perlodonLlLls are tetracyc||nes
W long wlL anLlmlcroblal acLlvlLy @@ agenLs
ave Le ablllLy Lo lnlblL
neuLroplls
osLeoclasLs and
maLrlx meLalloproLelnases LaL
appear Lo be lnvolved ln Le desLrucLlon of Le
perlodonLlum ngman 1 orsa 1
W @eLracycllnes ave an anLllnflammaLory acLlon
and may be bonesparlng Lroug lnlblLlon
of osLeoclasLs Iern|||o A1 kamamurthy -
W oxycycllne ls Le mosL sLudled and sLrongesL
collagenase lnlblLor of Le used LeLracycllnes
o|ub LM orsa 1 Lee nM
Ant|nammatory Drugs
W racldonlc acld meLabollLes are
prolnammaLory medlaLors bone resorpLlon
J||||ams kC Ieffcoat Mk
W @ese medlaLors can be lnlblLed by nSs
suc as
asplrln lbuprofen and naproxen
W nlblL Le enzyme cyclooxygenase Lereby
prevenLlng Le producLlon of aracldonlc acld
meLabollLes
onepar|ng Agents
W lsposponaLe bonesparlng agenL as been
lncorporaLed ln Le managemenL of
osLeoporosls and
oLer boneresorpLlve dlseases
ato M rasser J
W @ey are absorbed by Le bones and locally
released durlng acldlcaLlon assoclaLed wlL
osLeoclasLlc acLlvlLy
W lsposponaLes lnlblL bone resorpLlon by
reduclng osLeoclasL acLlvlLy
ato M rasser J
W @erefore Ley may ave a poLenLlal role ln
Le lnlblLlon of alveolar bone loss ln
perlodonLlLls paLlenLs and around lmplanLs
L|pox|ns
W ndogenous llpldderlved medlaLors
W 8eleased ln Le course of Le osL response Lo dampen
Le lnflammaLory process and modulaLe resoluLlon of
lnflammaLlon
Ian Dyke erhan 2003
W n Lls conLexL Lxs were ldenLlfled and recognlzed as
endogenous blocklng slgnals for Mn
D|amond et a| 1999 ou||ot et a| 2000
n|story
W Llpoxlns were flrsL descrlbed by erhan
namberg and amue|sson |n 1984
W @ey reporLed LaL Le llpoxlns sLlmulaLed
superoxlde anlon (C2-) generaLlon and
degranulaLlon aL submlcromolar
concenLraLlonsas poLenL as L@
W L presenL Lwo llpoxlns ave been ldenLlfled
1 llpoxln (Lx)
2 llpoxln (Lx)
|osynthes|s
W Llpoxlns are derlved enzymaLlcally from
aracldonlc acld an 6 faLLy acld
W n analogous class Le resolvlns are derlved
from and P 3 faLLy aclds
Char|es - erhan Mats namberg and
engt amue|sson
W noLer analogous class Le eplllpoxlns are
formed by nonenzymaLlc peroxldaLlon
|o|og|ca| act|v|ty
W Llpoxln slgnallng Lroug Le Lx8 lnlblLs
1 cemoLaxls
2 LransmlgraLlon
3 superoxlde generaLlon and
nl acLlvaLlon
Ch|ang - Ar|ta M and erhan C- %200S)
W Slmllarly Lo Le leukoLrlenes Lx wlll form Le
cysLelnylllpoxlns LxC Lx and Lx
owe|| J Chung D rave| %199S)
W subnanomolar concenLraLlons Lx and Lx
lnlblL leukoLrlenesLlmulaLed lnLeracLlons of
uman neuLroplls and endoLellal cells
apay|ann| A erhan C- rady nk %1996)
W Llpoxlns are lg afflnlLy anLagonlsLs Lo Le
cysLelnyl leukoLrlene recepLor Lype 1 (CysL@1)
W @e CysL@1 recepLor ls also Le slLe of acLlon for
Le asLma drug monLelukasL
Drazen I srae| L
n reso|ut|on
W urlng lnflammaLlon cells dle by apopLosls
W s parL of resoluLlon llpoxlns slgnal macropages Lo Le
remalns of Lese cells (pagocyLosls)
M|tche|| 1homas narvey k et a| %2002)
W urlng Le acuLe lnflammaLory process Le
prolnflammaLory cyLoklnes suc as @nl and L1 can
lnduce Le expresslon of anLllnflammaLory medlaLors
suc as llpoxlns and L wlc promoLe Le resoluLlon
pase of lnflammaLlon
McMahon |a|th|n and odson Cather|ne
L|pox|n ana|ogues
W SLable synLeLlc analogues of Lxs and asp|r|n
tr|ggered 1Sep|LkA4s %A1Ls) can mlmlc many
of Le deslrable anLllnflammaLory pro
resoluLlon acLlons of naLlve Lxs
McMahon M|tche|| rady nk %2001)
n I|tro and n I|vo tud|es
W ou||ot erhan 1999 appllcaLlon of Lx analogues Lo
murlne alr pouces drasLlcally reduced @nlasLlmulaLed
leucocyLe LransmlgraLlon concomlLanLly sLlmulaLlng L
ln pouc exsudaLes
W ou||ot et a| 2000 orpyromonas glnglvalls was
lnLroduced ln Le dorsal alr pouc @e admlnlsLraLlon
of sLable analogues of Lx and of @L blocked neuLropll
mlgraLlon lnLo Le alr pouc cavlLy and decreased C2
levels wlLln cellular exudaLes
W ou||ot et a| 2000 kantarc| et a| 2003 oL sLudles
provlded evldence LaL Lx was presenL ln Le CCl
and was generaLed by glnglvallsexposed neuLroplls
from sub[ecLs wlL locallzed aggresslve perlodonLlLls
suggesLlng LaL Lls llpld medlaLor may be lnvolved ln
lnflammaLory responses assoclaLed wlL speclflc forms
(eg aggresslve) of perlodonLlLls
W CollecLlvely daLa ave sown LaL llpoxlns are capable
of prevenLlng glnglval lnflammaLlon and bone loss ln
anlmal experlmenLal perlodonLlLls
MMs
W CalclumdependenL zlncconLalnlng
endopepLldases
W 8esponslble for Le Llssue remodellng and
degradaLlon of Le exLracellular maLrlx (CM)
lncludlng
collagens elasLlns gelaLln
maLrlx glycoproLelns and
proLeoglycan
W MMs mlnlmally expressed ln normal
pyslologlcal condlLlons
W MMs are regulaLed by
ormones
growL facLors and
cyLoklnes
n|story of MMs
W escrlbed lnlLlally by Ierome ross and Char|es
Lap|ere (1962)
W Cbserved enzymaLlc acLlvlLy (collagen Lrlple
ellx degradaLlon) durlng Ladpole Lall
meLamorposls (by placlng a Ladpole Lall ln a
collagen maLrlx plaLe)
W @erefore Le enzyme was named as lnLersLlLlal
collagenase (MM1)
tructure
W @e MMs ave a common domaln sLrucLure
W @e Lree common domalns are
Le propepLlde
Le caLalyLlc domaln and
Le aemopexlnllke C Lermlnal domaln
C|ass|f|cat|on
W @e MMs can be subdlvlded ln dlfferenL ways
Lvo|ut|onary
W Dse of blolnformaLlc meLods Lo compare Le
prlmary sequences of Le MMs suggesL Le
followlng evoluLlonary grouplngs of Le MMs
MM19
MMs 11 1 13 16 and 17
MM2 and MM9
ll Le oLer MMs
unct|ona|
W @ese groups are Le
collagenases
gelaLlnases
sLromelyslns and
membraneLype MMs (M@MMs)
unct|on of MMs
W @e MMs play an lmporLanL role ln Llssue
remodellng assoclaLed wlL varlous pyslologlcal
and paLologlcal processes suc as
morpogenesls
anglogenesls
Llssue repalr
clrrosls
arLrlLls and
meLasLasls
W MM2 and MM9 are LougL Lo be lmporLanL
ln meLasLasls
W MM1 ls LougL Lo be lmporLanL ln reumaLold
and osLeoarLrlLls
W 8ecenL daLa suggesLs acLlve role of MMs ln Le
paLogenesls of orLlc neurysm
W xcess MMs degrade Le sLrucLural proLelns of
Le aorLlc wall
Act|vat|on
W ll MMs are synLeslzed ln Le laLenL form
%ymogen)
W @ey are secreLed as proenzymes and requlre
exLracellular acLlvaLlon
W @ey can be acLlvaLed ln vlLro by many
mecanlsms lncludlng organomercurlals
caoLroplc agenLs and oLer proLeases
nh|b|tors
W @e MMs are lnlblLed by speclflc
endogenous Llssue lnlblLor of
meLalloproLelnases (@Ms)
W comprlse a famlly of proLease lnlblLors
@M1
@M2
@M3 and
@M
W ynthet|c |nh|b|tors generally conLaln
a celaLlng group LaL blnds Le
caLalyLlc zlnc aLom aL Le MM acLlve
slLe LlgLly
W Common celaLlng groups lnclude
hydroxamates
carboxy|ates
th|o|s and
phosph|ny|s
W Doxycyc||ne aL subanLlmlcroblal doses lnlblLs
MM acLlvlLy
W L ls used cllnlcally for Le LreaLmenL of perlodonLal
dlsease
W L ls Le only MM lnlblLor LaL ls wldely avallable
cllnlcally
W Sold under Le Lrade name erlosLaL by Le
company Co||aenex
W Mlnocycllne as also been sown Lo lnlblL MM
acLlvlLy
An|ma| stud|es on the effects of MM
|nh|b|tors on MM product|on and a|veo|ar
bone |oss
L|avaneras et a| %2001)
W Cral admlnlsLraLlon of a CM@8 and/or clodronaLe
(7 days )CM@8 admlnlsLraLlon alone sowed sllgL
reducLlon ln MM8 MM9 and elasLase acLlvlLles
and bone loss Cnly comblned admlnlsLraLlon of
CM@8 and clodronaLe slgnlflcanLly reduced MMs
acLlvlLles and bone loss
W ezerra et a| %2002) LlgaLurelnduced experlmenLal
perlodonLlLls ln raLs wlL subcuLaneous ln[ecLlon of S(7
days) SlgnlflcanL dosedependenL reducLlon ln alveolar
bone loss and osLeoclasL numbers ln anlmals LreaLed wlL
S compared wlL conLrols
W kamamurthy et a| %2002a) nLraglnglval LSlnduced
experlmenLal perlodonLlLls ln raLs Comparlson of oral
admlnlsLraLlon of doxycycllne and flve dlfferenL CM@s (6
days) dmlnlsLraLlon of CM@s decreased synLesls of MM
2 and MM9 Le number of lmmunoposlLlve sLalned cells
for L1 L6 and @nl and alveolar bone resorpLlon
W kamamurthy et a| %2002b) nLraglnglval LS
lnduced experlmenLal perlodonLlLls ln raLs Cral
admlnlsLraLlon of Lwo lowmolecularwelgL
MM lnlblLors 8 days oL compounds reduced
acLlve and/or LoLal acLlvlLy of MM1 2 3 7
8 9 13 1 osedependenL lnlblLlon of
bone loss wlL boL drugs
|sphosphonate
WlsposponaLes(also called dlposponaLes)
WrevenL Le loss of bone mass used Lo LreaL
osLeoporosls and slmllar dlseases
WlsposponaLes Lwo posponaLe (C3)
groups and are slmllar ln sLrucLure Lo
pyropospaLe
W @ey reduce Le rlsk of osLeoporoLlc fracLure ln
Lose wo ave ad prevlous fracLures Je||s
Cranney A eterson I
W lsposponaLes lnlblL Le dlgesLlon of bone by
encouraglng osLeoclasLs Lo undergo apopLosls or
cell deaL Lereby slowlng bone loss Je|nste|n
k kobertson k Mano|agas C
n|story
W llrsL lnvesLlgaLed ln Le 1960s for use ln
dlsorders of bone meLabollsm
W @e lnlLlal raLlonale for Lelr use ln umans
was Lelr poLenLlal ln prevenLlng Le
dlssoluLlon of ydroxyapaLlLe
W @elr acLual mecanlsm of acLlon
demonsLraLed wlL Le lnlLlal launc
of osamax %a|endronate) by Merck
Chem|stry
W ll blsposponaLe drugs
sare a common C
backbone
W @e Lwo 3 groups
covalenLly llnked Lo carbon
deLermlne boL Le name
blsposponaLe and Le
funcLlon of Le drugs
W @e long sldecaln (82)
deLermlnes Le cemlcal
properLles mode of acLlon
sLrengL of blsposponaLe
drugs
W @e sorL sldecaln (81)
ofLen called Le ook malnly
lnfluences cemlcal
properLles and
parmacoklneLlcs
harmacok|net|cs
W bouL 30 ls excreLed uncanged by Le
kldney
W @e remalnder as a very lg afflnlLy for
bone Llssue and ls rapldly adsorbed onLo Le
bone surface
Mechan|sm of act|on
W blsposponaLe group
mlmlcs pyropospaLes
sLrucLure Lereby lnlblLlng
acLlvaLlon of enzymes LaL
uLlllze pyropospaLe
W lsposponaLe molecules
preferenLlally sLlck Lo
calclum and blnd Lo lL
W lsposponaLes accumulaLe Lo a lg
concenLraLlon only ln bones
W lsposponaLes wen aLLaced Lo bone Llssue
are lngesLed by osLeoclasLs
A 1|ssue |eve|
W ecrease bone Lurnover due Lo decrease bone
erupLlon
W ecrease number of new bone mulLlcellular
unlLs
W neL poslLlve wole body bone balance
Ce||u|ar |eve|
W decrease osLeoclasL recrulLmenL
W lncrease osLeoclasL apopLosls
W decrease osLeoclasL adeslon
W decrease depL of resorpLlon slLe
W decrease release of cyLoklnes by macropages
W ncrease osLeoblasLs dlfferenLlaLlon and number
C Mo|ecu|ar |eve|
W nlblLs mevalonaLe paLway (can resulL ln
perLurbed cell and lnducLlon of apopLosls)
W ecrease posLLranslLlonal prenylaLlon of C@
blndlng proLelns
C|asses of |sphosphonates
W @ere are Lwo classes of blsposponaLe
nconLalnlng
nonnconLalnlng blsposponaLes
W @e Lwo Lypes of blsposponaLes work
dlfferenLly ln kllllng osLeoclasL cells
-on-conta|n|ng b|sphosphonates
LldronaLe (ldronel) 1
ClodronaLe (onefos Loron) 10
@lludronaLe (Skelld) 10
-conta|n|ng b|sphosphonates
W amldronaLe ( redla) 100
W nerldronaLe 100
W ClpadronaLe 300
W lendronaLe (losamax) 300
W bandronaLe (onlva) 1000
W 8lsedronaLe (cLonel) 2000
W ZoledronaLe (ZomeLa clasLa) 10000
W nlLrogenous blsposponaLes acL on bone
meLabollsm by blndlng and blocklng Le
enzyme farnesy| d|phosphate synthase %)
ln Le PMCCo reducLase paLway (also
known as Le mevalonaLe paLway)
1herapeut|c C|ass|f|cat|on
W ntravenous |sphosphonates
amldronaLe
zoledronlc acld
W ra| b|sphosphonates
lendronaLe
8lsedronaLe
enerat|ons of |sphosphonates
W |rst enerat|on |sphosphonates
sorL caln molecules wlc lnlblL Le krebs cycle
Lypes
eLldronaLe
clodronaLe
W econd enerat|on
long caln molecules wlc lnlblL faLLy caln paLways
Lypes
pamldronaLe
avallable ln I form
alendronaLe
07 absorpLlon
W 1h|rd enerat|on
rlsedronaLe
6 absorpLlon
zo|endronate
avallable ln I form wlc can be glven on an annual basls
DA nd|cat|ons
1 revenLlon of osLeoporosls ln
posLmenopausal women
2 @reaLmenL of osLeoporosls ln men
3 @reaLmenL of glucocorLlcoldlnduced
osLeoporosls ln boL men women
1he uses of b|sphosphonates
W @e prevenLlon and LreaLmenL of
1 osLeoporosls
2 osLelLls deformans (ageLs dlsease of bone)
3 bone meLasLasls (wlL or wlLouL
ypercalcaemla)
mulLlple myeloma
3 prlmary yperparaLyroldlsm
6 osLeogenesls lmperfecLa and
7 oLer condlLlons LaL feaLure bone fraglllLy
An|ma| exper|ments on the effects of b|sphosphonate
adm|n|strat|on on |nf|ammatory med|ator |eve|s and
a|veo|ar bone |oss
W runsvo|d et a| %1992) ffecLs of blsposponaLe
admlnlsLraLlon on cllnlcal parameLers and alveolar bone
loss durlng llgaLurelnduced experlmenLal perlodonLlLls
(Monkey) SysLemlc alendronaLe (16 weeks) SlgnlflcanL
reducLlon ln bone denslLy canges ln Le alendronaLe
group compared wlL Le placebo group Cllnlcal
parameLers (L C ) were noL slgnlflcanLly affecLed by
alendronaLe admlnlsLraLlon compared wlL placebo
W Je|nreb et a| %1994) ffecLs of blsposponaLe admlnlsLraLlon on
alveolar bone loss durlng llgaLurelnduced experlmenLal
perlodonLlLls (Monkey) SysLemlc alendronaLe lendronaLe
slgnlflcanLly reduced bone loss assoclaLed wlL experlmenLal
perlodonLlLls compared wlL conLrol anlmals
W ho[| et a| %199S) ffecLs of blsposponaLe admlnlsLraLlon on
alveolar bone resorpLlon durlng llgaLurelnduced experlmenLal
perlodonLlLls (8aL) SysLemlc rlsedronaLe slgnlflcanLly reduced
alveolar bone resorpLlon and loss of bone mlneral conLenL
compared wlL conLrol anlmals
W Iuan A oya%2006) ffecL of @oplcal dmlnlsLraLlon of
Monosodlum ClpadronaLe on xperlmenLal erlodonLlLls ln 8aLs
group and group plus Loplcal admlnlsLraLlon of C ( +
C) @e conLralaLeral slde ln boL groups served as unLreaLed
conLrols (C and C) respecLlvely @e LreaLed group ( + C)
exlblLed marked lnlblLlon of bone loss CsLeoclasLs ln Le C
LreaLed group were deLaced from Le bone surface were round ln
sape and exlblLed a loss of polarlLy and lack of ruffled borders
C||n|ca| stud|es on the effects of b|sphosphonate
adm|n|strat|on
W Ieffcoat keddy %1996) arallel arm randomlzed placebo
conLrolled Lrlal 0 pLs wlL cronlc perlodonLlLls SysLemlc
alendronaLe 10 mg/day for 6 monLs S8 9 monLs lacebo group
0 of slLes losL bone elgL @esL group 20 of slLes losL bone
elgL (p300)
W kocha et a| %2001) arallel arm randomlzed placeboconLrolled Lrlal
0 wlL cronlc perlodonLlLls and @ype 2 dlabeLes SysLemlc
alendronaLe 10 mg/day for 6 monLs @esL group 13mm dlfference
ln bone elgL (p30003) and 032 083mm CL galn (p30013)
compared wlL placebo
W L|h|nnaw| L|1antawy %2003) arallel arm randomlzed placebo
conLrolled Lrlal 2 pLs wlL cronlc perlodonLlLls SysLemlc
alendronaLe 10 mg/day for 6 monLs SlgnlflcanL dlfference (po0001)
ln bone mlneral denslLy of maxllla and mandlble no slgnlflcanL
dlfference ln C and CL
W 1aka|sh| et a| %2003) Case reporL women wlL cronlc
perlodonLlLls SysLemlc eLldronaLe 200 mg/day for 2 weeks aL
lnLervals of 6 monLs Crdlnary denLal LreaLmenL 3 years followup
mprovemenLs ln cllnlcal parameLers ( and LooL moblllLy) and ln
alveolar bone denslLy
W Mar[or|e k Ieffcoat%2007) fflcacy of blsposponaLes for Le
conLrol of alveolar bone loss ln perlodonLlLls n paLlenLs wlL
perlodonLal dlsease recelvlng propylaxls alendronaLe 70 mg once
weekly was well LoleraLed buL dld noL ave a deLecLable effecL on
alveolar bone loss excepL ln Lose paLlenLs wlL low mandlbular
M aL basellne
W nk Ieena Deepak rasad%2010) valuaLlon of an
amlnoblsposponaLe (alendronaLe) ln Le managemenL of
perlodonLal osseous defecLs gel based drug dellvery sysLem of
lendronaLe was formulaLed lollowlng surglcal flap
debrldemenL 01 ml alendronaLe gel placed lendronaLe was
more effecLlve ln lmprovlng cllnlcal and radlograplc parameLers
compared Lo placebo
W a|omo Leena DD %2011) s longLerm blsposponaLe Lerapy
assoclaLed wlL beneflLs Lo Le perlodonLlum ln posLmenopausal
women? lsposponaLe users ad lger plaque score lower
problng depL and lesser cllnlcal aLLacmenL loss compared wlL
Le conLrols
Ant|resorpt|ve doseresponse re|at|onsh|ps
across three generat|ons of b|sphosphonates
W flrsL generaLlon analogues ave anLlresorpLlve
acLlvlLy aL dose levels from 01 Lo 10 mg /kg
W second generaLlon of blsposponaLes @elr
anLlresorpLlve acLlvlLy ln growlng raLs ranges
from 001 Lo 1 mg /kg
W 3
rd
generaLlon sows anLlresorpLlve acLlvlLy ln
growlng raLs as low as 0001 mg /kg|etsema
Jk Lbet|no n a|vagno AM evan IA
AA tatement on |sphosphonates
1 Dsed ln Le 8x of osLeoporosls cancer
2 ocLors prescrlbe lnLravenous blsposponaLe
Lerapy for paLlenLs wlL cancer
3 merglng researc ls explorlng Le ablllLy of
lnLravenous blsposponaLe Lerapy Lo lnlblL
Le spread of some cancers Lo Le bone
ocLors also prescrlbe an oral dose of
blsposponaLes for paLlenLs aL rlsk for
osLeoporosls
Adverse effects
Common
W Cral blsposponaLes can cause
sLomac upseL
lnflammaLlon and eroslons of Le esopagus
W nLravenous blsposponaLes can glve fever and
flullke sympLoms afLer Le flrsL lnfuslon
W lsposponaLes ave been assoclaLed wlL
osLeonecrosls of Le [aw (Cn!)
W L as been suggesLed LaL blsposponaLe
LreaLmenL sould be posLponed unLll afLer any
denLal work Lo ellmlnaLe poLenLlal slLes of lnfecLlon
Joo ne||ste|n I ka|mar I %2006)
W MM 2 may be a candldaLe gene for
blsposponaLeassoclaLed osLeonecrosls of Le
[aws Lehrer Montazem A kamanathan L
%Ian 2009)
W 8ecenL sLudles ave reporLed blsposponaLe use
(Lo be speclflc zo|edronate and a|endronate) as a
rlsk facLor for aLrlal flbrlllaLlon ln women
neckbert k L| Cumm|ngs k
W Cne sLudy esLlmaLed LaL 3 of aLrlal flbrlllaLlon
cases mlgL ave been due Lo alendronaLe use
neckbert k L| Cumm|ngs k m|th -L
W l as noL yeL conflrmed a causal relaLlonslp
beLween blsposponaLes and aLrlal flbrlllaLlon
Longterm r|sks
W Dnusual fracLures ln Le femur of Le bone
W LongLerm blsposponaLe use can resulL ln
oversuppresslon of bone Lurnover
W @e rlsk of oesopageal cancer lncreased wlL
10 or more prescrlpLlons for oral
blsposponaLes and wlL prescrlpLlons over
abouL a flve year perlod reen I Czanner keeves
Jatson I J|se L era| I %2010) ra| b|sphosphonates and r|sk of cancer of
oesophagus stomach and co|orectum casecontro| ana|ys|s w|th|n a Uk pr|mary care
cohort , 341
CM1s
W Cemlcally modlfled Lo ellmlnaLe Lelr
anLlbacLerlal efflcacy
W 8eLaln osL modulaLory anLlcollagenolyLlc
effecLs
W @e flrsL cemlcally modlfled LeLracycllne
(CM@) was descrlbed ln 1987*
*o|ub L M 1 Mc-amara DAnge|o k A reenwa|d and -
kamamurthy 1987 nonanLlbacLerlal cemlcallymodlfled LeLracycllne lnlblLs
mammallan collagenase acLlvlLy ! enL 8es661310131
W @e mosL promlnenL caracLerlsLlcs of Lese
CM@s are
1 loss of anLlbacLerlal acLlvlLy
2 reLenLlon (or even enancemenL) of
Lelr efflcacy as lnlblLors of MMs
W 10 dlfferenL CM@s ave been developed 9 of wlc
lnlblL MMs and do noL possess anLlmlcroblal
properLles
W 10 CM@s screened ln vlLro all exlblLed anLlfungal
acLlvlLles*
W mong Lese compounds CM@313 3 and 308
were found Lo be Le mosL poLenL as anLlfungal
agenLs*
&u L|u Mar|a L kyan ns|M|ng Lee anford |mon eorge 1ortoraCaro|
Lauzon M|chae| k Leung and Lorne M o|ub A Chem|ca||y Mod|f|ed
1etracyc||ne %CM13) s a -ew Ant|funga| Agent Ant|m|crob Agents
Chemother 2002 May 46%S) 144714S4
W SLrucLures of doxycycllne
and CM@3 noLe LaL for
CM@3 Le dlmeLylamlno
group aL Le rlng as
been removed resulLlng ln
Le loss of anLlbacLerlal
properLles*
&u L|u Mar|a L kyan A Chem|ca||y
Mod|f|ed 1etracyc||ne %CM13) s a -ew
Ant|funga| Agent Ant|m|crob Agents
Chemother 2002 May 46%S) 144714S4
W CMT-1 4-dcdImcthy!amInn tctracyc!Inc
W CMT-3 4-dcdImcthy!amInn sancyc!Inc
W CMT-4 7- ch!nrn - 4 - 4-dcdImcthy!amInn
tctracyc!Inc
W CMT-7 12a- dcnxy- 4-dcdImcthy!amInn
tcracyc!nc
W CMT-8 4-dcdImcthy!amInn dnxycyc!Inc
W CM@s 13 6 7 8 are effecLlve lnlblLors of
wlc CM@ 3 ls Le mosL poLenL compound
W CM@s 2 and affecLs MM8 buL noL MM 13
W CM@ 3 ls lneffecLlve
W Sub opLlmal dose of CM@8 a blspospanaLe (aldronaLe) suppress
perlodonLal desLrucLlon and LooL loss and ln oLer desLrucLlve
lnflammaLory dlseases suc as arLrlLls L|avaneras A et a|
2001
W kamamurthy et a| 2002 LesLed doxycyllne and 3 dlfferenL CM@#s Lo
prevenL MM medlaLed Llssue breakdown @elr resulLs sowed LaL
all 6 drugs lnlblLed erlodonLal breakdown ln followlng order of
efflcacy CM@ 8 CM@1 CM@ 3 Cx? CM@ CM@7
W ka[esh - ate| %1999) novel Mecanlsm of cLlon of Cemlcally
Modlfled @eLracycllnes nlblLlon of CCx2MedlaLed rosLaglandln

2
roducLlon Cemlcally modlfled LeLracycllnes (CM@s) suc as CM@
3 and 8 (buL noL CM@1 2 and 3) lnlblL boL nC and
C
2
producLlon ln LSsLlmulaLed murlne macropages bovlne
condrocyLes and uman osLeoarLrlLlsaffecLed carLllage wlc
sponLaneously produces nC and C
2
ln ex vlvo condlLlons
W Ma|tra ub|r k role of cemlcally modlfled LeLracycllne on Lnf
alpa and mlLogenacLlvaLed proLeln klnases ln sepsls CM@3
lnlblLed Le @nl level as well as p38 Mk acLlvaLlon
W LM o|ub nonanLlbacLerlal Cemlcallymodlfled @eLracycllne
nlblLs Mammallan Collagenase cLlvlLy @ls cemlcally
modlfled LeLracycllne (CM@) was found Lo lnlblL Le ln vlLro
acLlvlLy of collagenase from parLlally purlfled exLracLs of uman
reumaLold synovlal Llssue and raclLlc raL eplpysls
W LM o|ub n a prellmlnary ln vlvo sLudy paLologlcally
excesslve collagenase ln skln and glnglva was lnduced by
renderlng adulL male raLs dlabeLlc and Le oral admlnlsLraLlon of
CM@ Lo Lese raLs slgnlflcanLly reduced Le excesslve collagenase
acLlvlLy ln boL Llssues
W e|na a|ka||a and urm|t |ngha %2003) oxycycllne and oLer
LeLracycllnes ln Le LreaLmenL of bone meLasLasls doxycycllne
reduces Lumor burden ln a mouse model of breasL cancer
derlved osLeolyLlc bone meLasLasls
W and|er C -urm| k %200S) Cemlcally modlfled LeLracycllnes
lnduce apopLosls ln culLured masL cells @ey sLudled Le effecLs
of four dlfferenL cemlcally modlfled LeLracycllnes (CM@1 CM@
3 CM@8 and CM@308) on prollferaLlon and vlablllLy of culLured
mouse and uman masL cells ll sLudled CM@s (23 mlcroM)
effecLlvely lnlblLed Le vlablllLy and prollferaLlon of uman
masL cell llne (PMC1) cells and mouse bone marrow derlved
masL cells (mMMCs)
W u L|u%2002) Cemlcally Modlfled @eLracycllne (CM@3) s a
new nLlfungal genL @e MCs of CM@3 agalnsL 7 sLralns of
fungl ln vlLro were deLermlned by uslng ampoLerlcln (M)
and doxycycllne as poslLlve and negaLlve conLrols respecLlvely
W M M ||dt %2006) Cemlcally modlfled LeLracycllnes sLlmulaLe
maLrlx meLalloproLelnase2 producLlon by perlodonLal llgamenL
cells MM2 producLlon was sLlmulaLed up Lo sevenfold by CM@
1 3 7 and 8 aL low concenLraLlons (10200 lM) no slgnlflcanL
amounLs of MM9 were produced n conLrasL MM2 and 9
acLlvlLy was reduced by 100fold aL lger concenLraLlons (200
300 lM) CM@3 ad no effecL on Le producLlon or on Le acLlvlLy
of MM2 and 9 Cnly CM@3 and 8 ad cyLoLoxlc effecLs on Le
L cells aL Le lgesL concenLraLlons
W runa L %2011) nLeracLlon of cemlcally modlfled LeLracycllnes
wlL caLalyLlc Zn() lon ln maLrlx meLalloproLelnase evldence for
meLal coordlnaLlon slLes @e resulLs suggesLed LaL C1Cam of
CM@1 CM@ and CM@7 was Le mosL sLable slLe ln Le gas
pase and aqueous soluLlon Powever for CM@3 and CM@8
coordlnaLlon aL Le C11C12 moleLy (slLe I) was preferred
8esulLs supporL Le slngular beavlor of CM@3 and CM@8 as
promlslng MM lnlblLors
Conc|us|on
W @ere are slLuaLlon ln wlc convenLlonal Lerapy
does noL always acleve Le dlseased cllnlcal
ouLcome
W n Lese lnsLances and for speclflc groups of
perlodonLal dlsease suscepLlble lndlvlduals Le use
of PM@ ln con[uncLlon wlL convenLlonal
LreaLmenLs may prove Lo be advanLageous
W s meLods LaL modulaLe Le osL response
become avallable Ley may be useful as ad[uncLlve
Leraples for a varleLy of cllnlcal slLuaLlons
8eferences
W 1 Mlcael S 8eddy nlco C Ceurs and !on C Cunsolley erlodonLal
PosL ModulaLlon wlL nLlproLelnase nLlnammaLory and one
Sparlng genLs SysLemaLlc 8evlew nn erlodonLol Iolume 8
number 1 ecember 2003
W 2 SleLsema Wk beLlno lP Salvagno M evan ! nLlresorpLlve
doseresponse relaLlonslps across Lree generaLlons of
blsposponaLes rugs xp Clln 8es 198913(9)38996
W 3 8a[eswar Ierma and Corwln Pansc MaLrlx meLalloproLelnases
(MMs) Cemlcalblologlcal funcLlons and (C)S8s loorganlc
Medlclnal CemlsLry 13 (2007) 22232268
W 8 C8PM C 8DSSLL MCPL ! 8CC8S @e armacology
of lsposponaLes and new nslgLs nLo @elr Mecanlsms of
cLlon [ournal of bone and mlneral researc Iolume 1 SupplemenL
2 1999
W 3 Salvl C Lang n PosL response modulaLlon ln Le
managemenL of perlodonLal dlseases ! Clln erldonLol 2003
32 (Suppl 6) 108129
W 6 Manllo @olomeo SLefanla Crlmaudo ecLs of cemlcally
modlfled LeLracycllnes (CM@s) ln senslLlve mulLldrug reslsLanL
and apopLosls reslsLanL leukaemla cell llnes rlLls !ournal of
armacology (2001) 133 306 31
W 7 l m golub L f mcnamara g dangelo r a greenwald2
and n s ramamurLy nonanLlbacLerlal Cemlcally
modlfled @eLracycllne nlblLs Mammallan Collagenase
cLlvlLy ! enL 8es 66(8)1310131 ugusL 1987
W 8 ModulaLlon of Le PosL 8esponse ln erlodonLal @erapy !
erlodonLol 2002736070
W 8a[es n aLel novel Mecanlsm of cLlon of Cemlcally
Modlfled @eLracycllnes nlblLlon of CCx2MedlaLed
rosLaglandln
2
roducLlon 1be Iootool of lmmoooloqy
1999 163 339367
W LM Colub @l Mcnamara C ngelo 8 Creenwald and nS
8amamurLy nonanLlbacLerlal Cemlcallymodlfled
@eLracycllne nlblLs Mammallan Collagenase cLlvlLy I uN1 k5
1987 66 1J10
W Zelna Salkalla and CurmlL Slnga (2003) oxycycllne and oLer
LeLracycllnes ln Le LreaLmenL of bone meLasLasls
W Sandler C nurml k (2003) Cemlcally modlfled LeLracycllnes
lnduce apopLosls ln culLured masL cells nL mmunoparmacol
2003 CcL3(11)161121
W lldL MM SnoekIan eurden M eCrooL ! Ian l kul[pers
!agLman M Ion den Poff !W Cemlcally modlfled LeLracycllnes
sLlmulaLe maLrlx meLalloproLelnase 2 producLlon by perlodonLal
llgamenL cells ! erlodonL 8es 2006 1 6370
W runa L Marclal Lulz nLonlo S CosLa Wagner e lmelda
Cleber nconl Pello l os SanLos nLeracLlon of cemlcally
modlfled LeLracycllnes wlL caLalyLlc Zn() lon ln maLrlx
meLalloproLelnase evldence for meLal coordlnaLlon slLes @eor
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