host modulation

2.  Introduction
 Inflammation- concepts of host modulation
 Matrix metalloproteinases- (MMP) -Possible stages of MMP inhibition
 Tetracyclines and their analogues
 Sub antimicrobial dose of Doxycycycline
 Chemically modified Tetracyclines
 AA metabolites –Prostanoids -Antiinflmmatory drugs
 Bisphosphonates
 Cytokines and Anti-cytokine therapy
 Vaccination
 Resolution of inflammation – Lipoxins, Resolvins, Protectins
 Growth factors
 Probiotics, Prebiotics
 Conclusion

3. INTRODUCTION
Periodontal disease is a multifactorial, complex disease,
& an upregulated or maladapted Immune-inflammatory
response to bacterial plaque predisposes patients to
periodontal breakdown.

4.  Host response in periodontal disease acts as a dual edged sword,
it is protective, but same time its over response or an altered
response considered to be destructive to periodontium.
 Periodontal disease always initiates with the microorganisms,
so it is considered to be an infection, but, most of the destruction
occurs or continued later is because of that immuno-
inflammatory process triggered by this bacteria

5.  It is thus logical to consider therapeutic approaches that
modulates this host response (HOST MODUALTION) so that
destruction can be minimized by using them as an adjunctive
to non surgical or surgical periodontal therapy.
 Concept of host modulation: Williams & Golub et al
(1990,1992)

6.  Host:
• “A living organism or plant affording subsistence or lodgment to a
parasite.
• An individual into which a tissue, part, or embryo is transplanted from
another”.
 Host response : represents the reaction of the body of
living animal or plant against invading or threatening factors

7.  HOST MODULATION – “the alteration of function or
status of the host , in response to a stimulus or an altered
chemical or physical environment”
Host modulation therapy (HMT) – is a
treatment concept that aims to reduce the tissue destruction
and stabilize or even regenerate the periodontium by
modifying or down regulating destructive aspects of the host
response and up regulating protective or regenerative
responses

8. It may be that we are attempting to alter the natural
mechanism of the host which is always to be done cautiously,
because there is always a balance between one process to the
other, changing one process by therapeutic approach may be
harmful to the host

9. Overall HMT should not “switch off” normal defense
mechanisms or inflammation, instead they ameliorate excessive
or pathologic elevated inflammatory response to enhance the
opportunities for wound healing and periodontal stability

11. Complementary treatment strategies in periodontitis

12. Mechanisms of connective tissue matrixMechanisms of connective tissue matrix
destruction in Periodontitis-destruction in Periodontitis- Role of hostRole of host
modulationmodulation
o Tissue remodeling is usually tightly regulated by a complex
interplay of cell- cell and cell- matrix interactions, involving
the production of enzymes, activators, inhibitors, and
regulatory molecules such as cytokines and growth factors.

13. o The ENDOPEPTIDASES (PROTEINASES) are the key
enzymes in tissue degradative processes, since the protein
components of the most matrices are the predominant tissue
structure and function
o Matrix macromolecules can be degraded by proteinases from
the four major classes (metallo, serine, cysteine and
aspartic active residues)

14. o Matrix metalloproteinses ( MMP’s ) are a family of 23
endopeptidases ( Clark et al 2008)
o They are called as matrixins, sometimes incorrectly referred to
as simply, collagenases

15. o They are mainly, but not exclusively synthesized by connective
tissue cells.
o They can also be synthesized by hemopoitic cells, monocytes and
macrophages, keratinocytes and endothelial cells.
o They are METAL BINDING proteinases secreted as PRO ENZYME
forms, requires extra cellular activation

16. 16
All MMP’s have similar multi-domain
structure: Ryan et al 1996)
“Pre” region to target for secretion,
“Pro” region to maintain latency,
Catalytic region that contains the
active zinc-binding site.
Proline-rich hinge region, which
supposedly provides conservation of the
zinc-binding site.

17. First major sub group
 Interstitial collagenases ( MMP-1, MMP-8, MMP-13)
 MMP-1(collagenase 1)- from connective tissue cells and
macrophages
 MMP-8 – from PMNs
 MMP- 13(collagenase 3)- from human chondrocytes

18. Second Major sub group
 Gelatinases ( MMP-2 and 9 also called as type IV collagenase)
 MMP- 2- from mesenchymal cells
 MMP- 9 – from PMNs, macrophages and stimulated
connective tissue cells

19. Third and fourth major sub groups
 Stromeolysins (MMP-3, 10 & 11)- secreted by stromal cells
 Membrane bound group( MMP-14, 15 &17)
 Metrilysin (MMP- 7) and metalloelastse(MMP-12) do not fit
into any of the above groups.
……….In summary

20. Classes and properties of human
MMP’s
GROUP MMP
NUMBERING
OTHER NAMES SOURCE MATRIX
SUBSTRATES
COLLAGENASES MMP-1 CL-1 fibroblast Type I,II, III, VII,
VIII, & X
Proteoglycans
MMP-8 CL-2 Neutrophil
MMP-13 CL-3 chondrocytes
GELATINASES MMP-2 GLA Mesen . Cells Type IV, V, VII,X
&XI, Elastin
MMP-9 GLB PMN’s, macroph
STROMELYSINS MMP-3 SL-1 STROMAL CELLS Type x ,
xi,proteoglycan,
laminin,
elastin,procollag
en I,II,III
MMP-10 SL-2
MMP-11 SL-3
Membrane
bound
MMP14,15,16,17 MTI MMP Stromal cells Progelatinase

21. Activation of MMPs at cell surfaces
o MMP’s are secreted in latent
proforms
o Plasmin (serine proteinsases),
derived from plasminogen by the
action of plasminogen activator
effective in activation of
collagenase

22. Control of activity of MMPs by tissue
inhibitors of MMPs
o Imbalance between the tissue inhibitors of MMPs and
MMPs are responsible for the tissue degradation
o 60 different MMP inhibitors have been pursued as clinical
candidate till today (Dorman, 2007) among them…..

23. TIMP’s
α-2
MACROGLOBULIN
ENDOGENOUSENDOGENOUS
INHIBITORSINHIBITORS
Pericellularly
Body fluids

24. Zn2+
and Ca2+
-chelating agents
Phosphorus containing peptides
Sulfur based inhibitors
Hydroxamic acid inhibitors

25. Hydroxamic acid inhibitorsHydroxamic acid inhibitors
The hydroxamate group of these derivatives binds to the Zn2+
at the active site of enzyme
capable of inhibiting MMPs 1, 2, 3, 7, 8 and with very low
levels of inhibitors

26. Hydroxamic acid inhibitors
Batimastat in rats – Bjornsson et al 2004 .

27. Tissue Inhibitors of Metalloproteinases ( TIMP’s)
• Four types
o TIMP – 1, 2, 3, & 4
o TIMP-acts by Disruption of
the disulfide bonds of
MMPs- loss of activity of
MMPs

28. Other factors controlling the MMPs
Increases
IL-1 alpha
TNF- alpha
Decreases
Transforming growth
factor
Fibronectin and fibronectin
fragments

29. MMPs and Periodontitis
o Collagenase activity increased in GCF of periodontitis patient
than the healthy subjects (Larivee J et al)
o Most of the collagenase are PMNs derived, than tissue derived
(Villela B et al)
o Lower levels of TIMPs in periodontitis group compare to healthy
group (Lee et al)

30. Possible stages for intervention(host modulation)
in matrix degradation involving MMPs
Blocking the actions of agents that induce MMPs
Prevention of the translation of MMP messages
Blocking the activation of proenzyme forms of MMPs
Inhibition of active MMPs
Up-regulation of natural inhibitors (TIMPs) and
combination

31. • Blocking the actions of agents that induce
MMPs
o Blocking the Prostanoids and IL- alpha which induces
MMPs .
o By anti-inflammtory drugs & phorbal esters

32. • Blocking the activation of Proenzyme forms of MMPs
o New group of drug - series of “isothiazolones”- inhibit
cartilage proteoglycan degradation without decreasing
synthesis, utilizing the above mechanisms

33. • Up-regulation of TIMPs
o In vitro studies they have shown , utilizing the TGF-b, fibroblast
growth factor ,retinoids helped in up-regulating TIMPS
o Fang et al, utilized direct transfer of osteogenic plasmid genes to
stimulate new bone formation. Similar approach could be used
to up-regulate TIMPS by gene transfer

34. • Inhibition of active Metalloproteinases ( latent MMPs)
o Tetracyclines including the semisynthetic analogues minocycline,
doxycycline are capable of inhibiting latent mmps
o This inhibitory effect is due to its capable of inhibiting mammalian
collagenase by its ability to bind to zn cations and as well as calcium
ions in the catalytic domain of the molecule
o However using tetracyclines and is analogues for the longer duration
results in bacterial resistance and systemic unwanted effects
o Among this doxycycline proved to better inhibitor of collagenase

35. Pleiotropic host modulation effect
of doxycycline

36. Mediated by extracellular mechanism
Direct inhibition of active MMPs by cation chelation (dependent
on Ca2+ and Zn2+binding properties)
Inhibits oxidative activation of latent MMPs (independent of
cation-binding properties)

37. Mediated by cellular regulation
Scavenges and inhibits production of reactive oxygen species
produced by neutrophils
Inhibits MMPs and reactive oxygen species thereby protecting
alpha 1-proteinase inhibitor, and thus indirectly reducing tissue
proteinase activity
Inhibit the expression of nitric oxide synthatase thus
overproduction of nitric oxide is reduced
Down regulates expression of key inflammatory cytokines (IL-1,
IL-6, TNF – alpha and PGE2 )

38. Mediated by pro – anabolic effect
 Stimulates fibroblast collagen production
 Reduces osteoclast activity and bone resorption
 Blocks osteoclast MMPs
 Stimulate osteoblastic activity and bone formation

39. DoxycyclineDoxycycline

40. Subantimicrobial ( LOW) dose of
doxycycline (SDD)
 It is the only commercially available host modulation drug for the
treatment of periodontitis, which is approved by FDA (Periostat &
oracea collagenax pharmaceuticals)
 Available as Doxycycline hyclate 20 mg tablet to be taken b. i. d
rather than 50 or 100 mg capsule typically administered as
commercially available antibiotics (Golub et al 1998)
 Several clinical studies have demonstrated improvements in
gingival healing when SDD is used in combination with SRP (Caton
et al 2000, 2001, Novak 2002, Preshaw et al 2004)

41.  NEW -Modified release subantimicrobial dose doxycycline
o 40 mg once daily with SRP rather than 20 mg b. d
o 9 month double blind randomized placebo controlled
multicenter study on 266 subjects
o There was statistical significance decrease in the probing pocket
depth and reduction in the B.O.P
o Showed similar results in their earlier study using
20 mg b.i.d
Preshaw et al (2008)

42.  Gopski et al (2009) did multicenter, prospective, controlled trial
utilizing SDD combined with the flap surgery for 12 month post
op. They also assessed ICTP (collagen telopeptide) & compared
it with the placebo
o Results- SDD with the flap surgery resulted in increased
attachment gain and inhibiting early stage bone resorption
 They also showed short term reduction in the ICTP level

43. SDD for special patient population
 SDD in periodontitis – associated genotype patient (IL-1SDD in periodontitis – associated genotype patient (IL-1
polymorphism)polymorphism)
o Al Shammari et al (2001) treated above patients with SRP alone and
SRP with SDD for 2 to 4 months
o They assessed the IL-1 b and MMP-9 level as biochemical marker
o There was no reduction in the above markers with the SRP alone, but
50 -61% decrease in this after SDD
o Correspondingly gain in attachment and reduction in PD - SDD
provides PST positive patients with a therapeutic benefit

44.  SDD – Generalized Aggressive periodontitis patients
o Novak MJ et al(2002) – studied 70 patients , in a 9 month,
double blind, placebo controlled study
o There was significant gain in probing depth reduction in pockets
of 7 mm or greater at base line as early as 1 month after therapy
o This effect was maintained 3 months after the stopping the drug
therapy, demonstrating the no rebound effect

45. SDD in Smokers
o Preshaw et al(2005) evaluated SDD in smokers and non smokers
and compared with the placebo for 9 months along with SRP
o Non smokers with SDD showed greatest improvement
o Smokers with SDD and nonsmokers with the placebo showed
the intermediate improvement
o Smokers with the placebo showed the poorest treatment
response
o Concluded that even patient considered traditionally resistant
for the SRP will benefit from the SDD

46.  SDD along with local drug delivery antibiotics
o Preshaw et al (2006) did a clinical trial of SDD + SRP along with
the Atridox and compared with the SRP alone
o Patients in the test group showed more than 2 mm
improvement in mean attachment gain and probing depth
reduction compared to SRP alone
o They concluded that combined therapy maximize the treatment
benefit and they also said that it is safe to use with LDD without
untoward effect

47. STUDY (Year) Duration Study Groups(N)
MEAN CAL CHANGE (mm)
MEAN PD REDUCTION
(mm)
% SITES WITH CAL
GAIN
% SITES WITH
PD REDUCTION
4–6 mm
Pockets
7+ mm
Pockets
4–6 mm
pockets
7+ mm
pockets
≥2 mm ≥3 mm ≥2 mm
≥3 m
m
Caton et al (2000)
Study: 9
months (drug:
9 months)
SRP + SDD (90) 1.03 1.55 0.95 1.68 46 22 47 22
SRP + placebo (93) 0.86 1.17 0.69 1.20 38 16 35 13
Novak et al (2002)
Study:9
months (drug:6
months)
SRP + SDD (10) 1.00 1.78 1.20 3.02 29 15 48 26
SRP + placebo (10) 0.56 1.24 0.97 1.42 21 11 21 6
Emingil et al (2004)
Study: 12
months (drug:
3 months)
SRP + SDD (10) 0.21 (all sites) 1.59 (all sites)
SRP + placebo(10) 0.05 (all sites) 1.32 (all sites)
Preshaw et al (2004)
Study: 9
months (drug:
9 months)
SRP + SDD (107) 1.27 2.09 1.29 2.31 58 33 62 37
SRP + placebo (102) 0.94 1.60 0.96 1.77 44 20 45 21
Lee et al (2004)
Study: 9
months (drug:
9 months
SRP + SDD (240) 1.56(all sites) 1.63 (all sites)
SRP + placebo (17) 0.80(all sites) 1.19 (all sites)
Choi et al (2004)
Study: 4
months (drug:
4 months)
SRP + SDD (15) 2.2test sites) 1.6 (test sites)
SRP + placebo (17) 0.6(test sites) 1.1 (test sites)

48. Study (Year) Duration Study Groups(N)
MEAN CAL CHANGE (mm)
MEAN PD REDUCTION
(mm)
% SITES WITH CAL
GAIN
% SITES WITH
PD REDUCTION
4–6 mm
Pockets
7+ mm
Pockets
4–6 mm
pockets
7+ mm
pockets
≥2 mm ≥3 mm ≥2 mm
≥3 m
m
Gurkan et al (2005)
Study: 6
months (drug:
3 months)
SRP + SDD (13) 1.12 2.15 1.80 3.38
SRP + placebo (13) 0.78 1.76 1.46 2.57
Preshaw et al (2005)
Study: 9
months (drug:9
months)
SRP + SDD(116) 1.23 1.89 1.22 2.16 59 33 63 37
SRP + placebo (135) 0.96 1.43 0.88 1.53 43 19 44 18
SRP + SDD(81) 1.03 1.71 1.01 1.80 44 21 45 20
SRP + placebo (60) 0.85 1.58 0.80 1.62 37 15 31 13
Mohammad et al
(2005)
Study: 9
months (drug:
9 months)
SRP + SDD (12) 2.14 3.18 1.57 3.22
SRP + placebo (12) 0.02 0.25 0.63 0.98
Górska and Nedzi-
Góra (2006)
Study: 3
months (drug:
3 months)
SRP + SDD (33) 0.33 (all sites) 0.29 (all sites)
SRP + placebo (33) 0.04 (all sites) 0.08 (all sites)
Needleman et al
(2007)
Study: 6
months (drug:
3 months)
SRP + SDD(18) 0.65 (all sites) 1.40 (all sites)
SRP + placebo (16) 0.40 (all sites) 0.98 (all sites)

49.  Indications
 Chronic periodontitis
 Disease resistant patients
 Patients with generalized aggressive
periodontitis
 Smokers and PST positive patients
 Contraindications
 H/o allergy or hypersensitivity to
tetracyclines
 Pregnant or lactate women
 Children less than 12 years
 Patient who on OC

50. SIDE EFFECTS:
• At antibiotic dose (>100 mg)
– Photosensitivity
– Hypersensitivity reactions
– Nausea
– Vomitting
– Esophageal irritations
• SDD (20 mg)
– Well tolerated
– Typical s/e not observed
– No evidence of antibiotic resistance

51. Sequencing prescription with
periodontal treatment
o SDD not to be used as a stand alone therapy
o It is combined with the first episode of SRP for 3 months up to a
maximum of 9 months
o For patient demonstrating the good response after the first 3
months plaque control therapy to be continued
o Risk category patients and patients do not respond to the initial
treatment SDD to be continued
o Patients may cycle between phases of active treatment ( SRP
+SDD ) and long term periodontal maintenance

52. Golub et al (1987) recognizing that the antimicrobial
and anticollagenase properties of tetracycline may
reside in different parts of the molecule

53. Golub and co-workers modified their experimental
diabetes protocol using tetracycline therapy and germ-free
rats to determine whether the Gram-negative microflora
increased collagenase levels.
The Diabetic Rat Model:

54. 54
Conventional Rats Gnotobiotic Rats
Periodontitis &
Diabetes
Minocycline
65% of pathologically excessive mammalian
collagenase activity was reduced.
Diabetes
Minocycline
70% of diabetic gingival collagenase
activity was reduced.

55. As a result of these initial studies, Golub et al. proposed:
(1) That tetracyclines, but not other antibiotics, can inhibit collagenase by
a mechanism not dependent on the drug's antibacterial efficacy &
(2) That this newly discovered property of tetracyclines could provide a
new approach to the treatment of diseases, such as periodontal
disease, & also including other (medical) disorders like rheumatoid and
osteoarthritis (as well as several cutaneous and other diseases) that
involve collagen destruction.

56. Chemically modified tetracyclines
(CMT)
o They modified the tetracycline by well known technique to
eliminate the antimicrobial part. They removed
DIMETHYLAMINO GROUP from the carbon-4 position of the A
ring of the four ringed (A,B,C,D) structure
Resulting structure is ……..

57. Chemical name- 4 de dimethyl amino tetracycline
(CMT)
CMT 1- 10 are found, among this
oCMT 1,3, 6, 7,8 – are effective inhibitors
oCMT- 3 is the most potent compound
oCMT -5 is ineffective
oCMT – 2, 4 inhibits MMP- 8, but not CMT -13

58. Beneficial effect
 Potent inhibitor of proinflammatory mediators,
 Increases the level of IL-10, an anti-inflammatory mediator
 Inhibit osteoclastic bone resorption and promote bone
formation
 Enhance wound healing
 Inhibit proteinase produced by periodontal pathogens
 Inhibits tumor cell invasion & attenuation of intimal
thickening after arterial injury

59. CMT’S

60. CMT’S

61.  Takai et al, treating diabetic rats by CMT-1, at 10 mg/d , 4
weeks , reduced the excess host collagenase activity and
decreased the clinical severity of gingival disease.
 Lavaneras et al (2001) treated LPS induced experimental
periodontitis, treated with the CMT- 8 alone or with the
clodronate.
CMT-8 alone resulted in slight reduction in MMP-
8, 9 and elastase activity. Combine administration resulted in
significant reduction in all of these.

62.  Ramamoorthy et al (2002) compared oral doxycycline and five
different type of CMTS in intragingival LPS induced
experimental periodontitis in rats
o After 6 days observation they found decrease in the MMP-2,
9, and other pro-inflammatory interleukins

63. Other MMP inhibitors
o Specific gelatinase inhibitor – possible role in cancer therapy
o Interferon gamma
o Combination of NSAID with proteinase inhibitor

64. Next generation MMP inhibitors
 The next generation MMPs should have specificity, which not
only of the catalytic domain (Zn and Ca binding), but also
should have role of extracatalytic motif in substrate binding
(preventing the loss of other substrates of c. tissue)
 There is an attempt to develop privileged structures, molecular
frameworks, bioisosteric / bioanalogues modification of MMPs

65. AA metabolites- prostaglandins
 The characteristics of a vasoactive fatty acid from human seminal
vesicles fluid capable of decreasing the blood pressure in rabbits
were first described by Von Euler (1939) – product was named as
prostagladins – assumed to originate from the prostate gland
o Its role in inflammation was only revealed in 1960’s
o Prostaglandin mediate bone resorption reported in 1970’s
o El attar et al . Goldhaber, Offenbacher – showed its role in
periodontal bone loss

67. Two isoformsof COX arerecognized
• COX-1 isexpressed
‘constitutively’
• Known asa
"housekeeping" enzyme.
• Functionsinclude
1. gastric cytoprotection
2. vascularhomeostasis
3. platelet aggregation
4. kidney function
• stimulated by hormonesor
growth factors
• COX-2 isusually
undetectablein most
tissues;
• itsexpression is‘inducible’
during statesof
inflammation
• Upregulated by pro
inflammatory cytokines,
endotoxin

68. o PG is composed of 10 classes, of which D,E,F,G,H and I are
biologically most important
o Among this PGE2 exhibits a broad range of prominent effects
o Numerous studies have indicated PGE₂ involved in the
pathogenesis of periodontal disease
o Goodson et al ,reported 10 fold increase of PGE₂ in inflamed
gingival tissue and
o Offenbacher demonstrated ↑level of PGE₂ in GCF of
periodontitis patients

69.  In vitro experiments
 Goldhaber et al (1973) added indomethacin a known inhibitor
of cox, to the culture media of diseased tissue showed
decrease in bone resorption up to 50 %
 Chang et al (2003) evaluated the role of cox-2 expression in
gingival fibroblasts stimulated with the nicotine and blocking
this by new cox-2 inhibitor NS- 398, however this new drug did
not show any protective effect, indicating that nicotine toxicity
was not directly related to COX- 2

70.  IN ANIMAL EXPERIMENTS
 Nyman et al (1979) studied the efficacy of indomethacin on
ligature induced periodontitis in beagle dog model.
Indomethacin delayed the onset and suppressed the
magnitude of the acute inflammatory response and decreased
the amount of bone resorption
 Several other systemic and topical preparation of various
agents like ibuprofen, mefenamic acid, piroxicam, naproxen,
ketoprofen has been shown the positive response

71. Studies in human -using systemic anti-
inflammatory agents
Reference Study design NSAID Perio
dmont
h
Outcome / results
Jeffcoat
etal
15 Refractory
patients
Flurbiprofen
50 mg b.d
2 Significant less bone loss
Jeffcoat et
al
7 patients with RPP Naproxen
500 mg b d
3 Substraction
radiography – bone gain
Reddy et
al
SRP + NSAID Meclofenama
te sodium 50
or 100mg b d
6 Substraction
radiography- bone gain
Flemming
et al
SPT patients ASA 500 mg
bd
3 CAL GAIN and ↓ in GI
Bissada SRP + NSAID Ibuprofen
800 mg /day
1.5 No beneficial effect

72. Systemic vs Topical
o Systemic NSAIDS resulted in several unwanted effects mainly GI
mucosa ulceration, increased sodium retention, reduced renal
blood flow, and eventually renal failure
o Topical preparation in the form of mouth washes, tooth pastes,
local drug delivery, irrigation agents are more useful and at the
same time it avoids the systemic unwanted side effects too
o Among the several agents FLURBIPROFEN is more useful
because of its unique property

73. Topical anti-inflammatory agents
- HMT
o Flurbiprofen and some other NSAIDS found to be lipophilic
and absorbs in the gingival tissues- topical application is
beneficial
o Several topical preparations has been tried with the positive
results compared to the systemic application

74. Studies in human -using anti-inflammatory
agents – topical
Reference Study design NSAID Perio
d
mont
h
Outcome/ result
Preshaw etal 42 moderately
advanced chronic
periodontitis
0.1%
ketorolac
moth rinse
6
week
↓ GCF – PGE2 level
Pacquette et
al
Adult periodontitis 4 diff conce
ketoprofen
dentifrice
12
month
Slows periodontal
destruction
Haesmann
et al
Experimental
gingivitis in man
Flurbiprofen
solution
irrigation
15
days
Reduced the severity of
gingival inflammation
Yewey et al Adult periodontitis Fluriprofen
with atrigel
-LDD
28
DAYS
↓ pocket depth, ↓BOP
Neeraj etal
(2004)
Department study
– localised
periodontitis
Flurbiprofen
gel .3 %
14
days
↓ G I

75. Triclosan – topical application
o Triclosan: non-ionic antimicrobial agent
o anti-inflammatory action
o antimicrobial action
o Inhibit:
o Cyclooxygenase &
o Lipooxygenase pathway
Thus may interfere with the products of AA metabolites
o Thus topical application of the anti-inflammatory agents
seems to be more promising in the future

76. Selective COX-2 inhibitor in HMT
 Traditional anti-inflammatory agents inhibit the progression
of periodontal disease, it is of interest that selective COX- 2
inhibitor are effective or not for the treatment of periodontal
disease
 Various studies showed that cox- 2 are efficacious as the
traditional anti-inflammatory drug

77. REFERENCE COX-2 INHIBITOR METHODS/RESULTS
BEZERRA et al
2000
INDOMETHACIN
AND MELOXICAM
LIGATURE PERIODONTITIS IN RATS –
PREVENTED BONE LOSS
LOBINI et al NS- 398 LIGATURE INDUCED PERIODONTITIS IN
RATS- REDUCED BONE LOSS
HOLZHAUSEN
et aL
CELECOXIB INHIBITED BONES LOSS IN SHORTER
PERIOD THAN 30 DAYS
BUDUNCIL et al MELOXICAM TENDENCY TO REDUCE THE MMP- 8 IN
GCF, WITHIN FIRST 10 DAYS
Vardar et al NIMESULIDE PGE 2 LEVEL DECREASED WITHIN 10
DAYS
GURGEL et al MELOXICAM POST TREATMENT EFFECT AFTER
DURG WITHDRAWL –
NO REMAINING EFFECT WAS SEEN
AFTER WITHDRAWL

78. o Looking at the results of short term studies, it is understood
that, cox-2 inhibitory agents are effective in the HMT
o Cox-2:
o Proinflammatory during the early phase of inflammation
o Aid in resolution at the later, mononuclear cell dominated phase
by generating an alternative set of anti-inflammatory
prostaglandins, PGD2 & PGJ2

79.  Later identified to be associated with significant & life
threatening adverse effects, resulting in some drugs being
withdrawn.
 In summary, selective cox-2 inhibitors are presently not
indicated as adjunct HMTs in the treatment of periodontal
disease.

80. References
• Clinical periodontology; 10th
Edition. Carranza
• Clinical periodontology; 11th
Edition. Carranza
• Clinical Periodontology & Implantology; 5th
Edition. Jan Lindhe
• Host-mediated resolution of inflammation in periodontal diseases
Periodontology 2000, Vol. 40, 2006, 144–163
• Cytokines and prostaglandins in immune homeostasis and tissue
destruction in periodontal disease.
PeriodontoIogy 2000. Vol. 14. 1997, 112-143
• Protective nature of host responses in periodontal diseases.
Periodontol 2000 1994;5:112-41.