This document provides information about host modulation therapy for periodontal treatment. It discusses how periodontal destruction results from the host inflammatory response, not just bacteria. Host modulation therapy aims to reduce tissue damage by modulating the host response. It describes how drugs like sub-antimicrobial dose doxycycline (SDD) and chemically modified tetracyclines (CMTs) can inhibit matrix metalloproteinases (MMPs) and reduce collagen breakdown. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also be used as they block prostaglandin production from arachidonic acid. The document outlines various clinical studies that demonstrate the effectiveness of these agents in reducing inflammation and bone/tissue loss

1. Under the esteemed guidance of ;-
Prof. Dr. SUHAIL MAJID JAN (HOD)
Dr. ROOBAL BEHAL (Associate Professor)
By:-
MUMTAZ ALI PG (2nd Year)
‘’DEPARTMENTOF PERIODONTICSANDORALIMPLANTOLOGY’’
GovernmentDental Collegeand hospital, Srinagar.
HOST MODULATION IN PERIODONTAL THERAPY
‘’Periodontal destruction in periodontitis
is the result of connective-tissue
degrading mediators that occurs as a part
of inflammatory response.’’
-Page (1997)

2. INTRODUCTION
PATHOGENESIS OF PERIODONTITIS
HOST MODULATION THERAPY
• SYSTEMIC
• OTHER HMT
• LOCAL
CONCLUSION
REFERENCES
CONTENT

3. INTRODUCTION
Modulation is defined as:-
The alteration of function or status of
something in response to a stimulus or an
altered chemical or physical environment.
-(Taber's Medical Dictionary, 2004)
Host can be defined as :-
The organism from which a parasite obtains its
nourishment," or
In the transplantation of tissue, "the individual
who receives the graft.“
-Carranza 13th edition.
The concept of host modulation is fairly new to the field of dentistry but is universally
understood by most physicians who routinely apply the principles of host modulation to the
management of chronic progressive disorders such as arthritis and osteoporosis

4. Introduced to dentistry by Williams (1990) and Golub et al (1992)
Host modulation is a ‘’treatment concept that aims to reduce tissue destruction and stabilize the
periodontium by ;-
Up regulating protective or regenerative components of
the host response.
Down regulating or modifying destructive aspects.’’

5. The plaque bacteria are necessary to initiate disease and drive chronic inflammatory
process, but its presence alone accounts for a relatively small proportion (20%) of the
variance in disease expression.
The major component of soft and hard tissue destruction associated with periodontal
disease is the result of activation of host immune-inflammatory response to bacterial
challenge.
-Kornman KS (1997),Ebersole JL (2000),Baker PJ (2002)…

6. This response is essentially protective in intent to combat the bacterial infection and to prevent
ingress of bacteria into tissues.
• The primary defense mechanisms control the infection, and
chronic inflammation may persist indefinitely.
Disease Resistant
• Inflammatory events extend apically and laterally to involve
deeper connective tissues, alveolar bone and cause
destruction.
Disease-Susceptible

7. HMT is a means of treating the host side of the host-bacteria interaction.
HMTs offer the opportunity for modulating or reducing this destruction by treating
aspects of the chronic inflammatory response.
HMTs are systemically or locally delivered pharamaceuticals used as adjuncts to
conventional periodontal treatments such as scaling and root planing (SRP) and
surgery.

8. PATHOGENESIS OF PERIODONTITIS
1960 – BACTERIAL MODEL
Implicated bacterial plaque deposits as the primary direct factor in
the development of periodontitis.
1970s and early 1980s
Specific bacteria were implicated in the causation of periodontitis.
The protective and destructive roles of the host responses became clear and distinction was apparent
between the role of the microbes & immunoinflammatory mechanisms in the pathogenesis of
periodontal disease

9. Late 1980’s & early 1990’s
Disease modifying risk factors were identified.
-Page RC & Kornman KS 1997

10. 2008 - BIOLOGICAL SYSTEMS MODEL
-Offenbacher
The ‘‘biologic systems model’’ approach argues for
elucidating
– Person-level exposures,
– genetic and epigenetic components,
– establishing the biologic phenotype
– to determine the clinical phenotype of periodontal
disease.

11. 2015- Contemporary Model of host-microbe interaction in the
pathogenesis of periodontitis. -CHAPPLE

12. WHAT CAN WE
MODULATE?

13. HOW CAN WE
MODULATE?
Mechanical Treatment
(SRP)
Antimicrobial adjuncts;
Local Delivery Systems.
+
NSAID’s
Periostat
Periostat
Anticytokine
Drugs
Bisphosphonates
Periostat

14. HOST MODULATION THERAPY
LOCAL
SYSTEMIC
OTHER HMT’s

15. SYSTEMICALLY ADMINISTERED HMT
Host modulating agents acting against MMPs
 SDD
 CMT
Against arachidonic acid metabolites
 NSAIDS
Lipid - inflammatory mediators
 Lipoxins, Resolvins, Maresins
Against cytokines
 Anticytokine therapy
Against bone resorption
 Bisphosphonates
Modulation of Nitric Oxide synthetase

16. HM agents acting against
MMPs

17. Matrix Metalloproteinase (MMP’S)
They are endopeptidases secreted by a variety of host cells, that play key roles in the
degradation of the extracellular matrix, basement membrane and modify the action
of cytokines as well as activation of osteoclasts.
ENDOGENOUS
• TIMPs
• α-2 MACROGLOBULIN
EXOGENOUS
• Zn2+ and Ca2+-chelating agents
• Phosphorus containing peptides
• Sulfur based inhibitors
• Hydroxamic acid inhibitors
Inhibitors of MMPs

18. To impede the destruction of host tissues synthetic
inhibitors of MMP as host modulating agents have
been developed.
It contain a chelating group, inhibiting MMPs by
binding to the catalytic zinc atom at its active site.

19. A new approach to non-antibacterial periodontal therapy is
the administration of specially prepared low-dose capsules
containing as low as 20 mg of doxycycline.
Introduced by Golub et al 1990
Sub Antimicrobial Dose Doxycycline (SDD)
only tetracycline based host modulating agent, has been approved
by FDA to be used as an adjunct to periodontal treatment.
PERIOSTAT (SDD–sub-antimicrobial dose of doxycycline)
(20mg BID for atleast 3month

20. Golub et al
1998
Wasil et al
1998
Rifkin et
al 1994
Golub et al
1998
Milano et
al 1997
Nip et al 1993,
Ditto et al 1994
Mechanism Of Action Of SDD;-

21. WHY….???
Doxycycline has much lower inhibitory concentration (IC50=15µM)
minocycline (IC50=190µM) or
tetracycline (IC50=350µM)
Burns et al. 1989
indicating that a much lower dose of doxycycline is necessary to reduce a given collagenase level by 50%
compared with minocycline or tetracycline
Doxycycline is the most potent collagenase inhibitor of commercially available TCs.
Doxycycline tends to be highly concentrated in GCF at
levels 5-10 times greater than serum and show
substantivity as they bind to the tooth structure & are
slowly released as active agent.
Pascale et al 1986
Doxycycline has been found to be more effective in blocking PMN-
type collagenase activity (MMP-8) than fibroblast-type collagenase
activity (MMP-l) (Golub et al. 1995, Smith et al. 1999),
suggesting that doxycycline can provide a safe therapeutic method
for reducing pathologically elevated collagenase levels without
interfering with normal connective tissue turnover.
(Yanagimura et al., 1989).
Collagenase activity was inhibited by 70% in the presence of doxycycline, 45%
with minocycline, and 23% with tetracycline

22. CLINICAL STUDY ON SDD
(Golub et al. 1990).
SDD administered for just 2 weeks inhibited collagenase
activity by 60-80% in the gingival tissues of patients with
chronic periodontitis.
Collagenase activity was also significantly reduced in GCF
collected from these patients.
(Golub et al. 1994).
Subsequent studies of relatively short duration (1-3 months) indicated that this dosing regimen could
prevent periodontitis progression without the emergence of doxycycline-resistant microorganisms or
other typical antibiotic side-effects
Thus, the concept was born that SDD (20 mg twice daily) could be used as an adjunct for treatment of
chronic periodontitis.

23. Golub et al 1997
In a key study, SDD was given to 12 patients with chronic periodontitis for 2 months following a course of
subgingival instrumentation. Six patients were prescribed placebo.
At baseline, months 1 and 2, GCF samples were collected and analysed for MMP8, MMP-13 and ICTP
(carboxy terminal peptide, a pyridinoline-containing fragment of type-l collagen).
statistically significant reductions in GCF
concentrations of ICTP, MMP-8 and MMP-13
compared with placebo.
This was the first study that demonstrated in
human subjects that SDD results in a
simultaneous reduction of elevated MMP
activity with a concomitant reduction in levels
of collagen degradation fragments.

24. (Gapski et al. 2004).
The clinical, biochemical and microbiological effects of SDD on the
modulation of wound, comparing access flap surgery with SDD
(20 mg bid for 6 months) or placebo in patients with advanced
chronic periodontitis
Postsurgical wound healing was significantly enhanced compared with
placebo.

25. Clinical Trials Of SDD
no antimicrobial effect could be detected during or following a 9-month treatment with 20 mg doxycycline
twice daily relative to placebo in terms of total bacterial counts, the normal flora, or in periodontal or
opportunistic pathogens.
(Caton 1999) (Walker et al. 1985, Walker 1996), Walker et al. 2000b). McNamara

27. Adverse Effect Of SDD
Doxycycline at antibiotic doses (≥ 100 mg) is associated with
adverse events including, among others,
Photosensitivity,
Hypersensitivity reactions,
Nausea, vomiting and
Oesophageal irritation.
(Caton et al. 2000, Preshaw et al. 2002)
In the two large clinical trials conducted in the USA, SDD (20 mg
doxycycline twice daily) was well tolerated.
The overall reported adverse event rate with SDD was only 0.15% with the
most common adverse events being
Dyspepsia (0.2%),
Rash (0.1 %),
Headache (0.1%) and
Diarrhoea (0.1%)
In summary, SDD is well tolerated with a very low frequency of adverse
events.

28. CHEMICALLY MODIFIDED TETRACYCLINE
(CMT);-
These are nonantibiotic tetracycline analogues have been modified to remove
all antibiotic properties, but it retains
Host modulatory, anticollagenolytic effects.
Removal of the dimethylamino group from the carbon-4 position of the ‘‘A’’
ring .
• The first CMT is 4-dedimethylamino tetracycline (CMT -1)

29. The Ca2+ and Zn2+ binding sites at the
carbonyl oxygen and the hydroxyl groups of
carbon-11 and carbon-12 positions are
responsible for the anti-collagenase action
of the CMTs.
10 different chemically
modified tetracyclines
are identified

31. The potency of the various TCs as MMP inhibitors appears to be
CMT-8 > CMT-1 > CMT-3 > doxycycline > CMT-4 > CMT-7.
CMT-3 and CMT-8
• Inhibits osteoclastic bone resorption
• Promotes bone formation
• Enhances wound healing, and
• Inhibits proteinases produced by periodontal pathogens
-(Greiner D et al 2002).
CMT-3 is the only compound effective against MMP-1.
In addition, CMT-3 and –8 are the most effective collagenase activity inhibitors and
CMT-8 is the most effective inhibitor of MMP-13 activity
-(Greenwald et al. 1998).

32. The anti-collagenase activity of CMTs is specific against the collagenase
produced from neutrophils but not the fibroblasts.
Does not affect the normal collagen turnover required to maintain the
tissue integrity.
-(Golub et al 1991)

33. Chemically modified tetracycline CMT-3 inhibits histamine
release and cytokine production in mast cells.
-Sandler et al (2005)
Inhibition of the key pro-inflammatory functions of mast cells by CMT-3 suggests its potential clinical
usefulness in the treatment of allergic and inflammatory disorders.

34. Properties Of CMT’S
The inhibition of mammalian collagenase (Golub et al., 1984)
The inhibition of neutrophil chemotaxis;
Increased fibroblast attachment to the root surface.
(Rompen et al., 1993; Somerman et al.,1988);
Anti-inflammatory effects due to the inhibition of prostaglandin synthesis, but only in
high doses. (ElAttar et al., 1988);
The inhibition of bone resorption;
(Ramamurthy et al., 1990; Birkedal-Hansen, 1993; Rifkin et al., 1994);
An enhancement of collagen synthesis.

35. HM AGENTS ACTING AGAINST
ARACHIDONIC ACID METABOLITES

36. The arachidonic acid metabolites include a variety of fatty acid derived compounds that are enzymatically
produced and released in response to local tissue injury.
HM AGENTS ACTING AGAINST ARACHIDONIC ACID METABOLITES

37. In the early 1970s, Paul Goldhaber and Max Goodson
began to implicate arachidonic acid metabolites as important inflammatory
mediators of the bone loss of periodontitis.
Dybvig et al. (1982)
validated that prostaglandins are important mediators of bone loss in
periodontitis.
NSAIDs block the activity of both cyclooxygenase isozymes (COX-1 and -2)
flurbiprofen, indomethacin, and naproxen
• inhibits gingivitis and progression of periodontitis.
In 1971 John Vane and colleagues
reported that aspirin and aspirin-like drugs, also called nonsteroidal anti-
inflammatory drugs (NSAIDs), interfered with the arachidonic acid
metabolite pathway by blocking the enzyme cyclooxygenase, thus
blocking the production of prostaglandins.

38. Utilizing the beagle experimental periodontitis model, Nyman et al examined
the modulation of arachidonic acid metabolites with systemic indomethacin
and reported that the NSAID indomethacin,
suppressed alveolar bone resorption and gingival inflammation in the beagle.
Williams and co-workers
were the first to report in vivo data on the effect of NSAIDs on the progression of naturally
occurring periodontal disease in an animal model.
Over a 12-month treatment period, the effects of the NSAID flurbiprofen were compared with a
placebo in aged beagles with naturally occurring periodontitis. The investigators combined
experimental agents with conventional nonsurgical and surgical treatment modalities.
Their results indicated that daily administration of 0.02 mg/kg flurbiprofen by mouth significantly
decreased the rate of radiographic alveolar bone loss at 3, 6, 9 and 12 months in both
surgically and nonsurgically treated animal groups when compared to baseline levels.
The rate of alveolar bone loss did not decrease significantly over the treatment period for placebo
treated animal groups

39. Jeffcoat et al. (1995)
compared - topical ketorolac,
- systemic flurbiprofen and
- placebo
for the inhibition of alveolar bone loss in adult
periodontitis in 55 patients over 6 months.
Ketorolac rinse preserved more alveolar bone
than systemic flurbiorofen at the dose
regimens utilized.
Sekino and Salvi (2005)
conducted a clinical trial with a crossover
design on 11 subjects to evaluate the effect
of systemic administration of ibuprofen on
gingivitis and de novo plaque formation.
Ibuprofen administered via the systemic
route has an effect on gingivitis but not on
de novo plaque formation.

41. GIT disturbance
Gastrointestinal hemorrhage
Renal impairment
Hepatic impairment
Rebound” phenomenon
DISADVANTAGES OF NASID’S AS HMT
X

42. HM AGENTS ACTING AGAINST
LIPID - INFLAMMATORY MEDIATORS

43. LIPID - INFLAMMATORY MEDIATORS
Lipoxins (LX) which are generated endogenously late in
inflammation from arachidonic acid, possess both
anti-inflammatory and pro-resolving potential
Among the other endogenous chemical mediators resolvins, protectins, and maresins have shown to mediate
resolution and counter-regulate excessive acute inflammation.
These are biosynthesized from precursors like
Omega-3 polyunsaturated fatty acids (PUFAs),
Eicosapentaenoic acid (EPA), and
Docosahexaenoic acid (DHA)
• via sequential steps involving lipoxygenases (LOX), and cyclooxygenases (COX).

44. DUAL ACTION
As reduction of neutrophil infiltration and
recruitment, by blocking cytokines and reactive
oxygen species generation, thereby preventing
connective tissue and bone loss.
Serhan et al. 2008

46. HM AGENTS ACTING AGAINST
CYTOKINES

47. HM AGENTS ACTING AGAINST CYTOKINES
Pro-inflammatory and anti-inflammatory cytokines hold a great
potential for controlling the adverse effects of the host
immune response, consequently HMT against cytokines
(cytokine therapy) may prove to be an effective strategy for
treating periodontal diseases.

48. 1. Cytokine receptor antagonist:
Binds to the receptor present on the target cell and prevents the
cytokine from binding to the target cell.
interleukin-1 receptor antagonist (IL-1ra) which is commercially
available as Kineret (Anakinra, Amgen)
ANTAGONIZING PRO-INFLAMMATORY CYTOKINES VIA
2. Anti-cytokine antibodies:
Anti TNF-α antibody: Adalimumab, Cetrolizumab pegol, Golimumab
Anti IL-6 antibody: Tocilizumab
Anti IL-15 antibody: AMG714
Anti IL-12 and IL-23 antibody: Ustekinumab
Anti IL-17 antibody: AIN457
3. Soluble cytokine receptors:
Binds to the cytokines in solution and prevents signalling.
sIL-1R, sTNF-R, sIL-6R are the soluble receptors against IL-1β, TNF-α and IL-6, respectively

49. DISRUPTING INFLAMMATORY
CELL-SIGNALLING PATHWAYS IN HMT

50. DISRUPTING INFLAMMATORY CELL-SIGNALLING PATHWAYS
To inhibit the production of pro-inflammatory cytokines and/or stimulate anti-inflammatory cytokine production.
Cell-signalling pathways like
• Mitogen Activated Protein Kinase (MAPK),
• Nuclear Factor-Kappa B (NFκB),
• Janus tyrosine kinase-signal transducer and activartor of transcription (JAK/STAT)
are dependent on a number of signaling-intermediate molecules for its uninterrupted functioning.
Targeting these pathways or the intermediate signalling molecules for their blockade with HMT may be more effective
than targeting specific cytokines.

51. MAPK pathway: The three main sub-families of mitogen-activated protein kinases (MAPKs) are extracellular-regulated kinases (ERK), c-
Jun N-terminal activated kinases (JNK) and p38 that mediate immune cell functional responses to different extracellular stimuli through
multiple receptors. The MAPK cascade consists of a series of three-tired protein kinases, a MAPK and two upstream components, MAPK
kinase (MAPKK) and MAPKK kinase (MAPKKK). Activation of the activating transcription factor; ELK, Ets-like transcription factor associated
kinase; MEK, MAPK/ERK Kinase; TAK, TGFb

54. Souza et al. (2012) have listed some of the inhibitors targeting
these signalling pathways that have been manufactured and have
demonstrated anti-inflammatory activity, these are:
• SD-282; SC-409; SB (SmithKline Beecham) - 242235; AW-814141; BIRB-796; VX-702
p38 inhibitors
• SP600125
c-Jun N-terminal kinases (JNK) inhibitor
• FR180204
Extracellular-Signal-Regulated Kinases (ERK)
inhibitor
• BMS (Bristol-Myers Squibb)-345541
NFκB inhibitor
• CP-690550 (Pfizer)
JK3 inhibitor

55. Lima et al. (2004) demonstrated the protective role of pentoxifylline
(PTX), a methylxanthine derivative, in experimental periodontitis as a
inhibitor of cytokine synthesis, mainly tumor necrosis factor (TNF).
Likewise, a number of intracellular signaling pathways involved in
osteoclastogenesis, activated upon RANK-RANKL binding are blocked
by osteoprotegerin (a natural inhibitor of RANKL), which acts as a
decoy and blocks the binding of RANKL to RANK.
Cochran DL 2008 demonstrated that the protective role of OPG has
also been supported by the association of disease severity with
an increase in RANKL ⁄ osteoprotegerin ratio at periodontally
inflamed sites.
Thus, modulation of the RANKL ⁄ RANK ⁄ osteoprotegerin axis via
pharmacotherapeutic agents may lead to an increase in
osteoprotegerin and a decrease in RANKL to a level consistent
with an equilibrium state between bone formation and bone
destruction.

56. Jin et al. 2007
demonstrated that systemic delivery of OPG-Fc
fusion protein inhibits alveolar bone
resorption in experimental periodontitis,
supporting the fact that RANKL inhibition
may represent an important therapeutic
strategy for the prevention of progressive
alveolar bone loss.
Bartold et al. 2010
indicated that RANKL inhibitors, such as a fully
human monoclonal antibody that specifically
targets RANKL currently available as denosumab
(Denosumab, Amgen) can lead to increased bone
mineral density and decreased bone resorption.

57. RECOMBINANT ANTI-INFLAMMATORY CYTOKINE ADMINISTRATION
Martuscelli et al. 2000
demonstrated that subcutaneous injections
of recombinant human IL-11
(anti-inflammatory cytokine) were able to
slow the progression of attachment and
radiographic alveolar bone loss in a
ligature-induced beagle dog model.

58. HOST MODULATING AGENTS ACTING
AGAINST BONE RESORPTION

59. BISPHOSPHONATES
BPs are pyrophosphate analogs that can suppress osteoclastic
bone resorption.
They are known to bind to hydroxyapatite crystals and prevent
their dissolution in addition to increasing osteoblast
differentiation and inhibiting osteoclast activation.

60. Giannobile WV 2008 has summarized and categorized the bone-specific actions of bisphosphonates at
TISSUE LEVEL
• decreases bone turnover due to inhibition of
bone resorption
• decreases the number of new bone
multicellular units resulting in a net positive
whole body bone balance
CELLULAR LEVEL
• decreases osteoclast recruitment
• osteoclast adhesion,
• depth of resorption site
• release of cytokines by macrophages along with
• increase in osteoclast apoptosis and osteoblast
differentiation and number
Mechanism Of Action Of Bisphosphonates

61. FDA has approved the use of BPs orally or intravenously in the management of Paget’s disease,
osteoporosis, and bone metastases.
Based on its bone-sparing properties there exists a possible use for bisphosphonates in the
management of periodontal diseases as well.
Shoji et al. in 1995 demonstrated that systemic administration of a bisphosphonate could
prevent alveolar bone resorption in rats with experimental periodontitis.

62. ADVERSE EFFECTS OF BISPHOSPHONATES
Some bisphosphonates have the unwanted effects of inhibiting bone calcification and inducing changes in
WBC counts.
Also, there have been recent reports of avascular necrosis of the jaws following bisphosphonate therapy, with the
resultant risk of bone necrosis following dental extractions
(Carter G et al)
At present there are NO BISPHOSPHONATE DRUGS that are approved and indicated for treatment of periodontal disease

63. MODULATION OF NITRIC
OXIDE SYNTHASE

64. MODULATION OF NITRIC OXIDE SYNTHASE
Nitric oxide is a free radical with important physiological functions of maintaining homeostasis.
Stimulates
pro-inflammatory
stimuli such as
endotoxins
increases
expression of the
inducible nitric
oxide synthase
enzyme (iNOS)
produces a large
amount of nitric
oxide (NO) and
peroxynitrite
acts beneficially
for the host as a
cytotoxic
molecule against
the invading
microorganism
DELETERIOUS EFFECTS TO
HOST
DNA damage,
lipid peroxidation,
protein damage, and
stimulation of
inflammatory cytokine
release.

65. Lohinai et al. 1998
demonstrated the protective effects of
mercaptoethylguanidine (MEG), which is a
selective inhibitor of iNOS, against bone
destruction in ligature-induced periodontitis
in the rat.
Leitao et al. 2005
proved that NOS inhibitors prevent alveolar
bone resorption in experimental periodontitis.

66. OTHER HOST MODULATORY THERAPIES

67. PROBIOTICS
They modulate cytokine secretion profiles,
influence T-lymphocyte populations,
protect against physiologic stress, and
enhance antibody secretion.
Teughels et al. 2011
concluded that probiotics might offer opportunities to
manipulate the oral microbiota, and periodontal health by
either direct microbiological interactions or by
immunomodulatory interactions.

68. PERIODONTAL VACCINES
George Hajishengallis
reported that toll like receptors (TLRs) may offer novel
targets for host-modulation therapy in periodontitis
since manipulation of TLR signalling may contribute
to control of infection or regulation of inflammation.
Synthetic or natural TLR agonists could serve as novel
periodontal vaccine adjuvants.
Yokoyama et al. in 2007
demonstrated that egg yolk antibody against
Porphyromonas gingivalis (IgY-GP) proved to be an
effective immunotherapeutic agent in the treatment
of periodontitis.
Choi et al. 2001
reported that prior immunization of mice to Fusobacterium
nucleatum modulated the host immune responses to
Porphyromonas gingivalis at the humoral, cellular and
molecular level.

69. NUTRIENTS
Nutrients, which include major extracellular antioxidants, like
vitamin C
vitamin E
Carotenoids
reduced glutathione and
omega 3 fatty acid
• act as modulators of inflammation by scavenging free radicals
La VD et al. 2009
have demonstrated that cranberry juice contains molecules that
inhibit MMPs, IL-6, IL-8, and PGE2 production by
lipopolysaccharide-activated gingival fibroblasts .
potential of being used as a novel host-modulating agent to
inhibit tissue destruction during periodontitis.

70. LOCALLY ADMINISTERED
HMT
 Enamel matrix proteins
 Triclosan
 BMP
 PDGF
 Bisphosphonates
 NSAIDs
 Hypochlorous Acid and Taurine-N-Monochloramine
 Cimetidine

71. ENAMEL MATRIX PROTEINS
Commercially available for the treatment of periodontal defects as Emdogain®
(Biora AB, Malmö, Sweden) which has received FDA approval.
The basic rationale behind using Emdogain is that it will act as a tissue-healing
modulator that would mimic the events that occur during root development
and help stimulate periodontal regeneration.
EMD initiates periodontal regeneration through recruitment of cementoblasts to the root-surface and stimulates
these to form root-cementum, which will thereafter secondarily lead to regeneration of periodontal fibers and
alveolar bone.
– justify its role as a host modulating agent.

72. TRICLOSAN
A compound which has received interest as both an antibacterial and anti-inflammatory
agent is Triclosan. (2, 4, 41-trichloro-2-hydroxy-diphenyl ether) a non-ionic antimicrobial
agent.
Triclosan also inhibits CO and LO pathway and thus may interfere with the production of AA
metabolites.
Use of a dentifrice containing sodium fluoride (0.243%) and triclosan (0.3%) reduced the frequency of deep
periodontal pockets and the number of sites exhibiting attachment and bone loss in patients deemed highly
susceptible to periodontitis.
(Rosling B et al 1997)
Additional studies are warranted to examine the effect of this combination of drugs on periodontitis.
At this time, the triclosan/copolymer dentifrice is indicated for the reduction of plaque, calculus, gingivitis,
and caries.

73. BONE MORPHOGENETIC PROTEIN
BMP guides modulation and differentiation of mesenchymal cells into bone and bone marrow cells.
Absorbable collagen sponge (ACS) containing recombinant human BMP-2 has been approved for clinical
use in certain oral surgery procedures, including localized alveolar ridge augmentation.
INFUSE® Bone Graft (Medtronic, Minneapolis, MN, USA)
InductOS™ (Wyeth, Maidenhead, UK).
These ACS release the protein over time in the location where it is
implanted and provides a scaffold on which new bone can grow. As
the graft site heals, the ACS is absorbed and replaced by bone.

74. PLATELET DERIVED GROWTH FACTOR
FDA has approved Growth-factor Enhanced Matrix, GEM 21S® (Osteohealth, Shirley, NY) which is a
combination of a bioactive highly purified recombinant human PDGF-BB with an
osteoconductive bone matrix.
PDGF, as a host modulating agent can cause
– fibroblasts proliferation and extracellular matrix synthesis,
– increase proliferation and differentiation of endothelial cells,
– stimulate proliferation of mesenchymal progenitor cells and
– differentiation of fibroblasts.
Nevins et al. 2005
demonstrated that the purified rhPDGF-BB mixed
with bone allograft resulted in robust
periodontal regeneration in both Class II
furcations and interproximal intrabony defects.

75. BISPHOSPHONATE
Studies using topically administered bisphosphonates have been carried out which have
reported a significant increase in the postoperative percentage of bone-defect fill
prevention of bone resorption as well as the boosting effect of locally delivered BPs on the
osteoconductive and regenerative potential of bone grafts used in periodontal therapy.
AR Pradeep et al. 2013
studied 1% alendronate gel as local drug delivery in the treatment
of Class II furcation defects
local delivery of 1% ALN into a Class II furcation defect
stimulated a significant PD reduction, CAL gains, and
improved bone fill compared with placebo gel as an adjunct
to SRP.

76. NSAIDs
NSAIDs are lipophilic and are well absorbed into gingival tissues, its topical
application is possible.
NSAIDs that have been evaluated for topical administration include ketorolac
tromethamine rinse and S-ketoprofen dentifrice, piroxicam and meclofenamic
acid in inhibiting gingivitis and progression of periodontitis.
Ketorolac tromethamine rinse(1%) (Jeffcoat et al
1995) & ketoprofen dentrifice (Paquette et al
1998) has improved clinical status &
decreased alveolar bone loss in adult
periodontitis.
Deshpande NC et al. 2013
evaluated the efficacy of novel indigenously designed
controlled release flurbiprofen gel system for
management of periodontal diseases
– local drug delivery of flurbiprofen through gel
media enhanced the positive effects of
scaling and root planing and helped in faster
resolution of the inflammation.

77. HYPOCHLOROUS ACID AND TAURINE-N-MONOCHLORAMINE
Lorenz et al. 2009
assessed the influence of 2 and 3% N-chlorotaurine mouth
rinse on dental plaque.
rinsing with 10 mL of the test solution two times daily for 4
days reduced the plaque vitality.
They are the end-products of the neutrophilic respiratory burst, modulates the host inflammatory response
by inhibiting the production of interleukin-6, prostaglandins, and other proinflammatory substances.

78. CIMETIDINE
It is a powerful H2-(Histamine) receptor antagonist, and hence eliminates
histamine’s effects on immune response, thereby acting as a modulator of
inflammation and immunity by inhibiting neutrophil chemotaxis and superoxide
production, increasing cyclic adenosine monophosphate (cAMP) levels
down-regulating cytokines.
Hasturk et al. 2006
provided morphological and histological evidence to prove that
topically active cimetidine is a potent inhibitor of P.
gingivalis-elicited periodontal inflammation and can arrest
and/or prevent tissue destruction and influence cell
populations present in the inflammatory cell infiltrate.

79. CONCLUSION
Host response modulators must be viewed as comprising part of the overall management strategy for
patients with periodontitis.
They should form part of an integrated treatment approach, together with hygiene therapy, plaque
control, root surface instrumentation, maintenance care and risk factor modification.
In the future, a range of HMTs targeting different aspects of the destructive cascade of breakdown
events in the periodontal tissues are likely to be developed, as adjunctive treatment for
periodontitis.

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81. THANK YOU