Professional Documents
Culture Documents
Therapy
PRESENTED BY: PALLAVI PRASHAR
MDS II YEAR
Introduction
• In the past, the understanding of the
etiology and the pathogenesis of the
periodontal disease focused on the
microbial aspect of the diseases and
thus, the therapeutic efforts focused
on the mechanical or the therapeutic
removal of the bacterial flora.
• Periodontitis can no longer be
considered a simple bacterial
infection that leads to periodontal
destruction. Rather, it represents a
collection of complex diseases
involving iterative interactions
between the host inflammatory and
immune systems, subgingival
microbiota and
environmental factors. modifying
• 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.
Host modulation • Means of treating the host side of the host-bacteria interaction.
therapy
• The purpose of HMT is to restore the balance of proinflammatory or destructive
mediators and antiinflammatory or protective mediators to that seen in healthy
individuals.
• HMTs offer the opportunity for modulating or reducing this destruction by treating
aspects of the chronic inflammatory response.
• HMTs do not “switch off” normal defense mechanisms or inflammation; instead, they
ameliorate excessive or pathologically elevated inflammatory processes to enhance
the opportunities for wound healing and periodontal stability.
• HMT is key to addressing many of the risk factors that have adverse effects on the
host response, which are either not easily managed (e.g., smoking, diabetes) or
cannot be changed (e.g., genetic susceptibility).
• In addition, host modulatory agents might be used to increase the levels of a
person’s own protective or antiinflammatory mediators.
• Use of systemic HMTs for treatment of a patient’s periodontal condition may also
provide benefits for other inflammatory disorders such as arthritis, cardiovascular
disease, dermatologic conditions, diabetes, rheumatoid arthritis, and osteoporosis.
• Hence, the Host Modulation Therapy offers the potential for the downregulating
destructive aspects and upregulating protective aspects of the host response so
that, in combinations with conventional treatments to reduce the bacterial burden,
the ‘balance’ is tipped in the direction of a healing response.
Host modulating agents
• COX-1 is a Primarily “Constitutive Isoform” found in Most Normal Cells & Tissues and have
Anti-thrombogenic & Cytoprotective Functions
COX-1 is expressed as the Dominant, Constitutive Isoform in Gastric Epithelial Cells &
is the major source of Cytoprotective PG Formation.
Inhibition of COX-1 at this site account largely for the Gastric Adverse Events
(Ulceration) and impaired hemostasis.
• Studies have shown that systemic NSAIDs such as indomethacin (Williams RC.
et.al, 1987), flurbiprofen (Williams RC.et.al, 1989) and naproxen (Howell TH, et.al,
1993) administered daily for up to 3 years significantly slowed the rate of alveolar
bone loss compared with placebo.
• However, NSAIDs have Some SERIOUS DISADVANTAGES when considered for
use as a HMT for Periodontitis.
1. Daily Administration for Extended Periods is necessary for Periodontal Benefits to
become apparent, & NSAIDs are associated with “Significant Side Effects”,
including
• GI Problems
• Hemorrhage (from Decreased Platelet Aggregation)
• Renal & Hepatic Impairment.
2. Research shows that the Periodontal Benefits of taking Long-term NSAIDs are
LOST when patients STOP taking the DRUGS, with a Return to or Even an
Acceleration of the Rate of Bone Loss seen Before NSAID Therapy, “Rebound
Effect.” (Williams, Jeffcoat, Howell 1991)
For these reasons, the Long-term Use of NSAIDs as an Adjunctive T/t for Periodontitis has
Never Really Developed Beyond Research Studies.
• Lipoxins (LX) which are generated endogenously late in inflammation via cell-cell interaction
when a second lipoxygenase (e.g. 5-LOX) interacts with a lipoxygenase product (e.g.
hydroxyeicosatetraenoic acid) generated earlier from archidonic acid, also possess both
anti-inflammatory and pro-resolving potential which have been summarized by Serhan et al.
• The Ca+2 and Zn+2-binding sites at the carbonyl oxygen and hydroxyl group of c-
11 and c-12 positions are responsible for anti-collagenase action of CMTs.
• Cytokine receptor antagonist: binds to the receptor present on target cell and prevent cytokines to bind to
the target cell. Eg. Interleukin-1 receptor antagonist.
• Anti-cytokine antibodies: Anti TNF a antibodies, Anti IL-6 antibody, Anti IL-15 antibody, Anti IL-12 and 23
antibodies.
• Disrupting inflammatory cell-signalling pathways
• Cell-signalling pathways like Mitogen Activated Protein Kinase (MAPK), Nuclear Factor-Kappa B (NFκB),
Janus kinase/signal transducers and activators of transcription (JAK/ STAT) and Receptor activator of
nuclear factor-kappa B (Rank)-Receptor activator of nuclear factor-kappa B ligand (Rankl)-Osteoprotegerin
(OPG) pathways are dependent on a number of signaling-intermediate molecules for its uninterrupted
functioning.
• Targeting these pathways or the intermediate signaling molecules for their blockade with HMT may be more
effective than targeting specific cytokines.
• It has also been seen that the activity of cytokines is also controlled by the suppressors of cytokine signaling
(SOCS -.SOCS-1, -2 and -3) messenger ribonucleic acid (mRNA), which when expressed, down-regulate
the signal transduction and inflammatory cytokine production as a part of an inhibitory feedback loop.
• Based on the clinical data 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:
• p38 inhibitors: SD-282, SC-409, SB (SmithKline Beecham) - 242235, AW-814141, BIRB-796 and VX-
702
• c-Jun N-terminal kinases (JNK) inhibitor: SP600125
• Extracellular-Signal-Regulated Kinases (ERK) inhibitor: FR180204
• NFκB inhibitor: BMS (Bristol-Myers Squibb)-345541
• JK3 inhibitor: CP-690550 (Pfizer)
As the BPs are Potent Osteoclast Inhibitors, their Long-term use may
Suppress Bone Turnover & Compromise Healing of Even Physiologic
Micro-injuries within Bone (Odvina et al 2005)
As with NSAIDs, at present there are No BPs Drugs that are approved & Indicated for T/t of Periodontal
Diseases.
• Furthermore, anti-integrins can also block the initial osteoclast adhesion to the matrix and
prevent bone resorption.
• Based on the well demonstrated role of estrogen on excessive bone resorption as well as
its lack in the post-menopausal osteoporosis affecting the remodeling of the bone tissue in
such a way that, in most patients with periodontitis the amount of bone resorbed exceeds
that being formed, resulting in net bone loss,
• Inagaki et al. has also suggested the use of selective estrogen receptor modulators
(SERM) and hormone replacement therapy (HRT) to improve the clinical outcome of
periodontal disease as an adjunctive treatment to preserve periodontal bone mass.
• Shu et al. in 2008 also demonstrated in human periodontal cells that estrogen may play a
significant role in modulating periodontal tissue responses to lipo-polysaccharide, and may
exert its bone-sparing effects on periodontal tissues via altering the expression
of
inflammatory cytokines.
• Yet, given the potentially large number of significant side-effects associated with hormone
replacement therapy, it is difficult to see this being recommended as a management
Lipid mediators of resolution of inflammation
• It is recognized that resolution of acute inflammation is a highly controlled process,
in which endogenous ‘pro-resolving’ mediators induce
• Cessation of leukocyte infiltration,
• Reduce vascular permeability and vasodilatation and
• Facilitate the safe removal and disposal of leukocytes (primarily by apoptosis) and the removal by
macrophages of apoptotic leukocytes, foreign matter (bacteria) and necrotic tissue
• These processes modify access of transcription factors to coding sections of DNA and
therefore influence gene expression and protein production.
• Studies of histone deacetylase inhibitors have identified that they have anti-inflammatory
properties in a number of chronic inflammatory and malignant diseases
• These agents posses potential anti-inflammatory properties, probably through
inhibition of the nuclear factor-B pathway and subsequent suppression of
inflammatory cytokines as well as inhibition of matrix metalloproteinase expression.
• The implication of these findings is that histone deacetylase inhibitors may hold
promise as novel therapeutics in the treatment of diseases characterized by bone
resorption, such as periodontitis.
• In the clinical studies conducted to date (in diseases other than periodontitis), they
have been shown to be well tolerated and safe, with evidence of clinical efficacy.
• Patient Compliance is Very Good because of the Short Course & the Low
Incidence of Side-Effects
Nutrients
• Nutrients, which include major extracellular antioxidants, like vitamin C, vitamin E,
carotenoids, reduced glutathione and omega 3 fatty acids can also act as modulators of
inflammation by scavenging free radicals as they are formed, sequestering transition metal
ions and catalyzing formation of other molecules.
• Studies have also demonstrated that cranberry juice contains molecules (A-type cranberry
proanthocyanidins: AC-PACs) that inhibit MMPs, interleukin-6, interleukin-8, and
prostaglandin E production by lipopolysaccharide-activated gingival fibroblasts and hence
show potential of being used as a novel host-modulating agent to inhibit tissue destruction
during periodontitis.
Periodontal vaccines
• Vaccination is a process that induces specific immune resistance to a bacterial or
viral infection.
• In the early twentieth century, three periodontal vaccines were employed, which
includes;
• Pure cultures of streptococcus and other organisms
• Autogenous vaccines
• Stock vaccines.
• Example includes Vancott's vaccine and Inava endocarp vaccine
• 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 and, moreover, synthetic or
natural TLR agonists could serve as novel periodontal vaccine adjuvants.
• Yokoyama et al. in 2007 also demonstrated that egg yolk antibody against Porphyromonas
gingivalis (IgY-GP) proved to be an effective immunotherapeutic agent in the treatment of
periodontitis.
Locally Administered Agents
• In addition, a number of local host modulatory agents have been investigated in clinical trials for
their potential use as adjuncts to surgical procedures, not only to improve on wound healing but also
to stimulate
• regeneration of lost bone, periodontal ligament, and cementum,
• restoring the complete periodontal attachment apparatus.
• 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.
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.
• Platelet derived growth factor (PDGF), as a host modulating agent can increase
chemotaxis of neutrophils and monocytes, stimulate 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 results in robust periodontal regeneration in both Class II furcations and
interproximal intrabony defects.
Bisphosphonate
• Role and action of BPs have already being discussed above.
• Due to serious side-effects of systemically administered BPs leading to
osteonecrosis of the jaws (ONJ) additional 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
Hypochlorous Acid and Taurine-N-Monochloramine
• It has been reported that hypochlorous acid (HOCl) and taurine-N-monochloramine (TauCl)
which are the end-products of the neutrophilic respiratory burst, modulate the
host
inflammatory response by inhibiting the production of interleukin-6, prostaglandins, and other
proinflammatory substances.
• Thus, HOCl and TauCl, playing a crucial role in the periodontal inflammatory process offer
opportunities for the development of novel host-modulating therapies for the treatment of
periodontitis.
• Recently, Lorenz et al. (2009) assessed the influence of 2 and 3% N-chlorotaurine mouth rinse
on dental plaque and demonstrated that rinsing with 10 mL of the test solution two times daily
for 4 days reduced the plaque vitality.
Cimitidine
• Cimetidine is a powerful H2-(Histamine) receptor antagonist, and hence eliminates histamine’s
inhibitory 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 and 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.
Summary and Conclusion
• The improved understanding of the host-bacterial interactions and the host
immuno-inflammatory response leading to periodontal tissue destruction has led
to the development of HMT.
• Though the efficacy and usefulness of host modulating agents have been
demonstrated by many clinical trials and have been approved by FDA for the
management of periodontitis, yet the risk/benefit ratio relating to the use of these
drugs has yet to be established.
• Multicenter clinical trials are necessary to fully evaluate the benefits of these
agents and to weigh their usefulness against the risks associated with their long-
term administration.
• Furthermore, continuous research in this field would also enable fabrication of
individualized treatment for periodontal disease targeting inflammatory host
response.
• The current article emphasizes the promising potential of various host-modulating
agents (the most crucial component of perioceutics) in the management of
periodontal diseases.