HOST MODULATION HOST MODULATION AND AGENTSAND AGENTS

• INTRODUCTION

• DEFINITIONS

• PATHOGENESIS OF PERIODONTITIS AND THE HOST RESPONSE

• HOST MODULATION THERAPY (HMT)– DEFINITION

– RATIONALE

- POTENTIAL TARGETS FOR HOST MODULATION

– SYSTEMICALLY ADMINISTERED AGENTS

– LOCALLY ADMINISTERED AGENTS

• SUBANTIMICROBIAL DOSE DOXYCYCLINE (SDD)

CONTENTS

• BISPHOSPHONATES

• MODULATION OF HOST CELL RECEPTORS

• MODULATION OF NITRIC OXIDE SYNTHASE (NOS) ACTIVITY

• CHEMICALLY MODIFIED TETRACYCLINES

• SUMMARY

• REFERENCES

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.

Recent therapeutic efforts focus on altering (modulating) the host response.

DEFINITIONSDEFINITIONS• Host – defined as……Host – defined as……

• Modulation – defined as the alteration of Modulation – defined as the alteration of function………function………

• The concept of host modulation- The concept of host modulation-

11stst –William(1990) – concluded from……indicating –William(1990) – concluded from……indicating that pharmacolgical agents that modulate the host that pharmacolgical agents that modulate the host response believed to be involved in………may be response believed to be involved in………may be efficacious in slowing the progression…..efficacious in slowing the progression…..

Golub etal (1992) – discussed HM with………Golub etal (1992) – discussed HM with………

Pathogenesis of PeriodontitisPathogenesis of Periodontitis

• The assessment of the role of the host response in the periodontal pathogenesis is required to better understand the host factors that are to be modulated.

Host-microbial interaction & Host-microbial interaction & the Host responsethe Host response

• Periodontal disease doesn’t appear to act as a Classic infection but, but more as Oppurtunistic infection ie when certain, more virulent species exist in an environment that allows for their presence in greater proportion, there is opportunity for periodontal destruction to occur

• Although, bacterial pathogens initiate the periodontal inflammation, the host response to these pathogens is equally imp in mediating connective tissue breakdown, including the bone loss.

Pathogenesis of Periodontitis Pathogenesis of Periodontitis

Schematic representationSchematic representation

Pathogenesis of periodontitis- Schematic representation

• Now, this response is essentially protective in intent, to combat the bact infection and prevent the ingress of bact into the tissues.

• In Disease- resistant individuals, these primary defense mechanisms control the infection and may persist as chronic inflammation .

• Where as in Disease- susceptible individuals, the inflammatory events extend apically and laterally to involve the deeper CT and alveolar bone.

Inflammation worsens

large no of PMNs migrate into the tissues

Secretion of Excessive quantities of destructive enzymes and inflammatory mediators

The enzymes includes MMPs, such as collagenases, which break down collagen fibres in the gingival and periodontal tissues.

disrupts the normal anatomy of the tissues

Macrophages are recruited to the area and are activated, by binding to LPS, to produce

PGs,

Interleukins(IL-1α,IL-1β, IL-6)

TNF-α

MMPs

• Concen of these enzymes and inflammatory mediators become pathologically high in the PD tissues

• Under healthy conditions, the elevations are counter-balanced by anti-inflammatory mediators (cytokines IL-4,IL-10,IL-1ra & tissue inhibitors of MMP(TIMP)

• Thus, keep the host response to bacterial challenge in check • And the individual is disease –resistant

In Susceptible patients, the excessive host response leads to an imbalance in disease and health of the periodontium

Periodontal BalancePeriodontal Balance

• Balance between the PD breakdown (disease) and the PD stability (health)

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 Modulation Therapy

• Defined as the treatment concept……….

• AIM:

To modify or reduce destructive aspects of the host response so that the immune inflammatory response to plaque is less damaging to the PD tissues

RATIONALE:

HMTs offer the oppurtunity for modulating or reducing destruction by treating aspects of the chronic inflammatory response.

Used as an adjuncts to conventional PD treatments (SRP & Surgery)

HMT’s do not “switch off” normal defense mechanisms or inflammation; instead they ameliorate excessive or pathologically elevated inflammatory processes to enhance the oppurtunities for wound healing and periodontal stability.

CMT’S

Host Modulation

Bisphosphonates

Potential Targets for Host modulationPotential Targets for Host modulation

Modulating agentsModulating agents

• A variety of different drug classes have been evaluated as Host Modulation agents:

• Systemically administered Agents:1. NSAIDs2. Bisphosphonates3. SDD (Subantimicrobial-Dose Doxycycline)

Locally administered Agents:1. Topical NSAIDs2. Enamel Matrix Proteins3. Growth factors 4. BMP5. Tetracyclines

Nonsteroidal Anti-inflammatory DrugsNonsteroidal Anti-inflammatory Drugs

PGE2

– upregulates bone resorption bv osteoclasts

– levels have been shown to be elevated in patients with periodontal disease

– inhibits fibroblast function

– inhibitory and modualtory effects on the immune response.

In addition to prostaglandins, other AA metabolites such as Prostacyclin appeared to be actively involved in bone resorption.

• NSAlDs inhibit the formation of prostaglandins, including prostaglandin E2 (PGE2)

NSAIDs include the – salicylates (e.g., aspirin)– indomethacin– propionic acid derivatives (e.g., ibuprofen,

flurbiprofen, naproxen).

• Studies have shown that systemic NSAIDs- administered daily for up to 3 years significantly slowed the rate of alveolar bone loss compared with placebo.

Disadvantages of NSAIDsDisadvantages of NSAIDs

– Daily administration for extended periods is necessary for periodontal benefits to become apparent

– Associated with significant side effects• gastrointestinal problems• hemorrhage (from decreased platelet aggregation)• renal and hepatic impairment.• “REBOUND Effect”

• Long-term use of NSAIDs as an adjunctive treatment for periodontitis has never really developed beyond research studies.

• In summary, NSAIDs (including the selective cyclooxygenase-2 (COX-2) specific inhibitors) are presently not indicated as adjunctive HMTs in the treatment of Periodontal disease.

Lipoxins (LXs):Lipoxins (LXs):

• Endogenous modulators of inflammation

• LXs are a class of both structurally and functionally unique eicasonoids involved in counter-regulation of inflammatory responses.

• These lipid mediators also appear to facilitate the resolution of the acute inflammatory response. In short, resolution of inflammation is an active process.

• LX and aspirin-triggered lipoxin (ATL) are bioactive lipid mediators involved in the AA cascade and are formed by the interaction of 5- and 15-LOs

• To counteract the known proinflammatory effects of PGE2 in periodontal disease, the potential protective contribution of lipoxins was investigated in the murine air pouch model (Pouliot et al. 2000).

• Collectively, data have shown that lipoxins are capable of preventing gingival inflammation and bone loss in animal experimental periodontitis.

BisphosphonatesBisphosphonates

• bone-seeking agents that inhibit bone resorption by disrupting osteoclast activity

• precise mechanism of action is unclear• research has shown that bisphosphonates

interfere with osteoblast metabolism and secretion of lysosomal enzymes.

• bisphosphonates also possess anticollagenase properties.

• modulate osteoclast activity

• Side effects

– inhibiting bone calcification– inducing changes in white blood cell counts– have been recent reports of avascular necrosis of the

jaws following bisphosphonate therapy, with the resultant risk of bone necrosis following dental extractions

• At present there are no bisphosphonate drugs that are approved and indicated for treatment of PD disease.

Subantimicrobial-Dose Subantimicrobial-Dose DoxycyclineDoxycycline

• 20-mg dose of doxycycline hyclate (Periostat) - approved and indicated as an adjunct to SRP in the treatment of chronic periodontitis.

• taken twice daily for 3 months, up to a maximum of 9 months of continuous dosing.

• The 20-mg dose exerts its therapeutic effect by enzyme, cytokine and osteoclast inhibition rather than by any antibiotic effect

• At present, SDD is the only HMT specifically indicated for the treatment of chronic periodontitis that is approved by the (FDA) and (ADA)

• SDD is used as an adjunct to SRP and must not be used as a stand -alone therapy (monotherapy).

• The tetracyclines have been used locally and systemically as antimicrobial agents and, more recently, systemically as a host modulation agent (Periostat).

• As an adjunct to mechanical therapies, the goal of tetracycline therapy has been to enhance reattachment or even to stimulate new attachment of the supporting apparatus and osseous formation.

Modulation of different pro-inflammatory pathways by Modulation of different pro-inflammatory pathways by DoxycyclineDoxycycline

Action….

Indications……Indications……

• in the management of Chronic Periodontitis and Aggressive Periodontitis.

• SDD can be used in patients with aggressive periodontitis who are being treated nonsurgically.

• Emerging studies have supported efficacy of SDD as an adjunct to periodontal surgery (Gapski et al 2004).

• SDD may also be of benefit in cases that are refractory to treatment, as well as in patients with risk factors such as smoking or diabetes, in whom the treatment response might be limited.

Contraindications……..Contraindications……..

• any patient with a history of allergy or hypersensitivity to tetracyclines.

• It should not be given to pregnant or lactating women

• children less than 12 years old - because potential for discoloration of the developing dentition

• Doxycycline may reduce the efficacy of OCPs, and therefore alternative forms of birth control should be discussed.

• There is a risk if increased sensitivity to sunlight (manifested by an exaggerated sunburn) seen with higher doses of doxycycline, although this has not been reported in the clinical trials using subantimicrobial dose.

Side EffectsSide Effects…..…..

• Doxycycline at antibiotic doses (≥100mg) is associated with adverse effects

• photosensitivity, • hyper-sensitivity reactions, • nausea, • vomiting,• esophageal irritation.

Various Studies…..Various Studies…..

• Studies using SDD therapy adjunctive to routine scaling and prophylaxis indicated continued reductions in the excessive levels of collagenase in the GCF after 1 month of treatment.

• After cessation of SDD administration, however, there was a rapid rebound of collagenase activity to placebo levels, suggesting that a 1-month treatment regimen with this host modulation agent was insufficient to produce a long-term benefit. (Ashley RA 1999)

• In contrast, during the same study, a 3-month regimen produced a prolonged drug effect without a rebound in collagenase levels to baseline during the no-treatment phase of the study.

• Golub et al. 1997 showed that a 2-month regimen of SDD significantly decreased both the level of bone-type collagen breakdown products and MMP-8 and MMP-13 enzyme levels (neutrophil and bone-type collagenase) in chronic periodontitis subjects

• The clinical relevance of such findings confirms the utility of an MMP inhibitor in the management of chronic periodontitis.

• More recent phase IV clinical studies have revealed success using SDD in particular populations of susceptible individuals.

Prescription with Periodontal Prescription with Periodontal TreatmentTreatment

• SDD is indicated as an adjunct to mechanical periodontal therapy and should not be used as a stand alone therapy.

• SDD should be prescribed to coincide with the first episode of SRP and is prescribed for 3 months, up to a maximum of 9 months of continuous dosing.

• Modification of any risk factors, such as smoking, nutrition, stress, contributing medications, faulty restorations, poor oral hygiene, and poor diabetic control, can also be addressed at this time.

• After initial periodontal treatment, the patient is enrolled into an intensive periodontal maintenance program

• At maintenance appointments, the need for further prescription of SDD can be assessed.

Combinations…..Combinations…..

• Combining with Periodontal Surgery SDD was used as an adjunct to access flap surgery in 24 patients

revealed better probing depth reductions in surgically treated sites greater than 6 mm compared with surgically treated sites in patients given placebo.

Combining with local Delivery Systems Preliminary results from a 6-month, 180-patient clinical trial

designed to evaluate the safety and efficacy of SDD combined with a locally applied antimicrobial (Atridox) and SRP versus SRP alone demonstrated that patients receiving the combination of treatments experienced more than a 2-mm improvement in mean attachment gains and probing depth reductions compared with SRP alone.

Modulation of Host Cell receptorsModulation of Host Cell receptors

• Cytokines are defined as regulatory proteins controlling the survival, growth, differentiation and functions of cells.

• Cytokines are produced transiently at generally low concentrations, act and are degraded in a local environment. This is documented by the fact that cytokine-producing cells are often physically located immediately adjacent to the responding cells.

• Moreover, the responding cell destroys the cytokine that it responds to in the process of receptor-mediated endocytosis.

• Several cytokines bind to elements of the extracellular matrix, thus restricting their spread beyond the site of action and increasing their bioavailability to the responding cells.

• Based upon the increased expression of IL-1 and TNF in inflamed gingiva and high levels in the GCF of periodontitis patients, several studies have suggested that increased production of these cytokines may play an important role in periodontal tissue destruction.

• To counteract tissue destruction and maintain homeostasis, cytokine antagonists such as IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptors can competitively inhibit receptor-mediated signal transduction (Dinarello 2004, Levine 2004).

• To prevent an uncontrolled inflammatory response with rapid tissue destruction, the activities of IL-1 &TNF-α are naturally counteracted by the production of cytokines- IL-4,10,11

• IL-11- has shown to inhibit the production of

IL-1β, TNF-α, IL-12 & NO in a no of inflammatory conditions.

Modulation of NOS ActivityModulation of NOS Activity

• Nitric oxide (NO) is a short-lived molecule implicated in a wide range of biological processes ranging from immune homeostasis to cancer (Brennan et al. 2003). It is synthesized in vivo from the substrate l-arginine by three isoenzymes called NOSs.

• While low levels of NO are present in tissue homeostasis, NO is produced at higher concentrations in response to inflammatory stimuli such as bacterial LPS via inducible forms of NOS (iNOS) (Southan & Szabo 1996).

• NO is a highly reactive free radical reacting with metal and thiol residues leading to lipid peroxidation, protein and DNA damages and stimulation of cytokine release (Brennan et al. 2003).

• An exaggerated production of NO has been implicated in the pathophysiology of several inflammatory processes such as arthritis, colitis and ileitis (Boughton-Smith et al. 1993, Middleton et al. 1993, Miller et al. 1995, Brahn et al. 1998).

• Animal experiments have shown that pharmacological inhibition of NOS with mercaptoalkylguanidines was associated with decreased inflammation, haemorrhagic shock and arthritis scores (Zingarelli et al. 1997, Brahn et al. 1998, Cuzzocrea et al. 1998).

Locally administered AgentsLocally administered Agents

Topical NSAIDs –• Have shown benefit in the treatment of periodontitis• Ketorolac mouth rinse has reported that GCF levels of PGEs were

reduced by approx half over 6 months• Not approved as local HMTs for management of periodontitis.

Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Proteins

– Enamel Matrix Proteins (Emdogain) - approved by the FDA for adjunctive use during surgery

– Bone Morphogenetic Proteins (BMP-2, BMP-7),

– Growth factors (platelet-derived growth factor, insulin-like growth factor)

• A number of local host modulation agents have been investigated for potential use as adjuncts to surgical procedures, not only to improve wound healing but also to stimulate regeneration of lost bone,PDL, and Cementum, restoring the complete periodontal attachment apparatus.

• The only local HM agent approved by FDA for adjuntive use is Emdogain

Tetracyclines are known to inhibit collagenases, but not all,

matrix metalloproteinases or MMPs from a variety of cells:

Neutrophils,

Macrophages,

Osteoblasts,

Chondrocytes, and

A wide range of tissues: skin, gingiva, cornea, cartilage, and

rheumatoid synovium.

TetracyclinesTetracyclines

• Tetracyclines inhibit PMN but not fibroblast collagenase

• It has been suggested that PMN’s provide the major

source of collagenase that mediates tissue breakdown during inflammatory periodontal disease,

• Fibroblasts contribute the collagenase required for CT

remodeling in normal gingiva. • Therapy with these drugs would be expected to reduce

pathologically elevated collagenolytic activity (e.g., during inflammation), but not the collagen turnover required to maintain normal tissue integrity.

Chemically Modified Tetracyclines Chemically Modified Tetracyclines (CMT’s)(CMT’s)

• To identify the site of the anticollagenase property, Golub and co-workers 1991, synthesized 10 different analogs of tetracyclines known as chemically-modified tetracyclines (CMTs 1-10).

• The proposed mechanism of action of CMT’s results from their ability to bind metal ions, particularly Ca2+ and Zn2+, which are required by enzymes to maintain its proper conformation and hydrolytic activity.

• Inhibition of active or pro-MMP could occur due to chelation of

Zn2+ ions resulting in disruption of normal conformation of protein structure

•

PMN’s Osteoblasts

Procollagenase

Collagenase

ROS e.g. HOCL by neutrophils

Secretes

Activated

CMT-1 100-400 µm

Inhibits 40 – 80%

TC effects on pro- collagenase activation:

SUMMARYSUMMARY

• The concept of periodontal medicine is emerging, in which the dentist treats not only the bacterial challenge (e.g., by SRP) but also the host side of the host-bacterial interactions.

• The use of HMTs such as SDD offers the opportunity to improve the treatment outcomes that can be anticipated following SRP alone.

• Patients must be encouraged and motivated so that they become an active participant in the management of their condition.

• HMT’s are an emerging treatment concept in the management of periodontitis.

• . In the future a range of HMTs targeting different aspects of the destructive cascade of breakdown events in the PD tissues are likely to be developed as adjunctive treatments for periodontitis.

• The further dev of these agents will permit dentists to treat specific aspects of the underlying biochemical basis for periodontal disease.

• The goal is to maximize the treatment response by reducing inflammation and inhibiting destructive processes in the tissues, which will result in enhanced periodontal stability after conventional periodontal treatments such as SRP.

• Carranza’s Clinical Periodontology 10th Edition• Host response modulation in the management of

periodontal disease. J Clin Periodontol 2005; 32(suppl 6):108-129• Modulation of the host inflammatory mediators as a treatment

strategy for periodontal diseases. Periodontology 2000, vol 24,2000,239-52

• Host modulation in periodontal therapy. Annuals periodontol 1998, vol 3:108-120

• Annuals Periodontol 2003, vol 8, no.1• Adjunctive benefits of SDD in the management of generalized

chronic periodontitis. J Periodontol 2002;73:762-769• Subgingival delivery of therapeutic agents in the treatment of

periodontal diseases. Crit Rev Oral biol Med 8(2):164-174(1997)

REFERENCES