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HOST MODULATION THERAPY

Contents
Introduction Risk factors Perioceutics Historical perspectives Host modulation
Host modulation options Classifications of agents Host modulation agents

Whom to treat with HMT? Conclusion References

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Introduction
Periodontitis-- chronic infectious diseases.

Plaque biofilm-- pathogenesis of periodontitis.

Microorganisms exert pathogenic effects

Direct

Indirect

Enzymes and cell wall components of bacteria:

destroy extracellular matrix activate osteoclastic resorption of bone.
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Clinical course vary -despite similar qualitative and

quantitative bacteria Gram negative infection of the pocket is necessary,--not sufficient to induce the periodontal disease initiation or progression .

Ultimately--it is the hosts reaction to the presence of

bacteria that mediates tissue destruction. Can also be influenced : Environmental Acquired Genetic risk factors.
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Extensive data indicate most extracellular matrix and

bone destruction in periodontitis is the result of

direct action of host-derived enzymes

cytokines, and other mediators.

RISK FACTORS The severity of periodontal diseases, its rate of progression and
its response to therapy varies from patient to patient. The host must be susceptible and it is the patients factors that determine susceptibility of the disease risk

.

Genetics Hormonal Stress Smoking Systemic diseases

Nutritional deficiency Medications Faulty dentistry Poor oral hygiene History of periodontal disease
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Host factor

Interference

Tissue destruction
Alter disease progression

PERIOCEUTICS
Use of pharmacological agents specifically developed to better mange periodontitis, is emerging to aid in the

management of susceptible patients who develop

periodontal disease. It includes
Antimicrobial therapies Host modulatory therapy that can be used to address a host
response consisting of excessive levels of enzymes, cytokines,
prostanoids & excessive osteoclast function that may be related to risk factors.
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Historical perspectives
As bacteria has been thought as main causative factor of
periodontitis, in the late 1970s and early 1980s, a few diverse research programs made out- standing progress that defined new opportunities for controlling periodontal disease by modulating the host response, instead of

directly controlling the bacterial challenge.

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The following were the major studies carried out: 1) Williams and colleagues (1985): using a beagle dog model of periodontal disease ,were able to demonstrate definitively that even in the presence of an excessive bacterial burden, it is possible to block disease progression significantly with a NonSteroidal Anti- Inflammatory Drug.

This finding also indirectly suggested : prostaglandins were

key players in the bone loss of periodontitis

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These investigators then examined the role of Prostaglandins in human periodontitis by blocking disease progression in subjects with periodontitis with the non steroidal anti-inflammatory drug Flurbiprofen. This was the first definitive proof that at least one specific host mechanism was in the critical path for periodontitis.

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2. Golub and coworkers showed that (a) Collagenase enzymes were an active component of the destructive process in periodontitis (b) Tetracyclines and analogues without antibacterial activity were able to inhibit collagenases. 3. Multiple investigators were exploring the ability of bisphosphonates to prevent bone destruction in osteoporosis The scientific successes of these parallel developments ultimately led to the clinical application of host-modifying agents as a therapeutic approach to the treatment of periodontitis

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HOST MODULATION
Host Modulation is a new term that has been incorporated into dentistry and has not been well defined.
From medical dictionary, Host the organism from which a parasite obtains its nourishment / in the transplantation of tissue, the individual who receives the graft. Modulation the alteration of function or status of something in response to a stimulus.
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Host modulation therapy:is a treatment concept that

aims to reduce tissue distruction and stabilize the

periodontium by modifying or down regulating disruptive aspects of the host response and up regulating protective or regenerative response.(Carranza) Various Host Modulatory Therapies (HMT) have been

developed or proposed to block pathways responsible for

periodontal breakdown.
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Anti-cytokine drugs
Antibody PMN Antigens Microbial challange LPS Other virulence factors Host immune Inflammatory Prostanoids response MMPs CT &bone metabolism Clinical signs of disease Cytokines

Antimicrobial adjuncts:local Delivery drugs

SDD CMTs Bisphosphonates

Mechanical treatment

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Classification of various host modulation therapies

Kenneth s kornman-1999

Host modulation 1: Block Direct Effectors of Bone and Connective tissue Destruction Eg :Bisphosphonates ,MMP inhibitors Host modulation 2: Blocking host mechanisms that influnces clinical outcomes Eg:NSAIDS,Inhibitors of TNF alpha Host modulation 3: Host mechanisms that influences bacterial control Eg:agents that reduce levels of PGE2,IL-1,TNF etc
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Salve G E ,Lang NP,2005

Modulation of arachidonic acid metabolites Eg:NSAIDS Modulation of MMPs Eg:TIMPs,Tetracyclines Modulation of bone remodelling Eg:Bisphosphonates Modulation of nitric oxide synthetase(NOS) Eg:Mercaptoethylglucanide
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Option 1: Block Direct Effectors of Bone and Connective tissue Destruction

The destruction of bone and connective tissue produces the clinical signs of disease, so perhaps the most direct opportunity for blocking destructive processes is at the level of osteoclastic bone destruction and destruction of connective tissues by MMPs.

Bisphosphonates MMP inhibitors

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BISPHOSPHONATES:
Bisphosphonates : potent inhibitors of bone resorption by osteoclasts Have an effect on osteoblasts. Bisphosphonates are analogues of pyrophosphate a potent inhibitor of bone resorption.
Structurally similar to pyrophosphate( a normal product of human metabolism present in serum and urine) has calcium-chelating properties
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HISTORY
Bisphosphonates :developed in the 19th century
Were first investigated in the 1960s for use in disorders of bone metabolism. The initial rationale for their use in humans :potential in preventing the dissolution of hydroxyapatite hence arresting bone loss.

Actual mechanism of action demonstrated only in the 1990s

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CHEMISTRY
Pyrophosphate is produced by many anabolic processes. It is rapidly hydrolyzed to its two constituent phosphate groups. If the linking oxygen atom in the pyrophosphate molecule is replaced by a carbon atom, a bisphosphonate is formed. These analogues are completely resistant to hydrolysis and are chemically extremely stable. Like pyrophosphate, they bind to the hydroxyapatite crystals of bone and prevent their dissolution.
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Classification
1. Based on the generation: First generation: with alkyl side chains E.g., etidronate Second-generation: amino-bisphosphonates with an amino-terminal group E.g., alendronate and pamidronate Third-generation: with cyclic side chains E.g., risedronate.
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2. Based on route of administration:

i. Orally Administered Bisphosphonates : e.g. Risedronate, Ibandronate, Alendronate, Tiludronate, Etidronate ii. Intravenously Administered Bisphosphonates e.g. Pamidronate, Zolendronic acid, Clodronate

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Association
Ronderus and colleagues (2000) reported that data from the NHANES III study suggested that osteoporosis is a risk factor for periodontitis. They observed more CAL in post menopausal women who did not receive estrogen therapy than in those who did.

Osteoporosis and periodontitis :- both are chronic diseases - prevalence in aging populations. -Involve osteoclastic bone resorption. Local production of cytokines appears to enhance osteoclastmediated bone resorption in estrogen-deficient patients. Peripheral blood monocytes from patients with osteoporosis secrete more interieukin-1 (IL-1).
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Both disease processes involves mast cells, neutrophils, macrophages, lymphocytes, and plasma cells.

Macrophages play an important role through the secretion of

interleukins 1, 6,8,10, and tumor necrosis factor-.

IL-6 is the most important cytokine in the recruitment of osteoclasts in abnormal osteoporotic bone remodeling.

Most importantly osteoporosis and periodontitis have these cytokines

in common.

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Mecahnism of action
A. Direct action on osteoclasts:
Bisphosphonate mediate inhibition of osteoclasts
Induction of osteoclastic apoptosis through activation of the capasase pathway. Reduction of activity of osteoclasts

Prevention of development of osteoclasts from haematopoietic precursors

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B. Indirect actions:
1- hydroxyethylidene-1, 1-bisphosphonate (HEBP) has osteostimulative properties both invitro and invivo HEBP mediated increases in matrix formation,, increased mineralized bone formation. HEBP treatment in vivo promotes osteoblastic differentiation in calvarial wounds, as well as a reversible stimulation of alveolar and calvarial bone width and reversible reductions in periodontal ligament space width.
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Bisphosphonate modulation of bone metabolism:

Tissue Level Bone turnover Bone resorption Number of new bone multicellular units Net positive whole body bone balance Cellular Level Osteoclast recruitment Osteoclast apoptosis Osteoclast adhesion Release of cytokines by macrophages Osteoblast differentiation and number

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Suppressies the interactions between the receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) . Bisphosphonates down regulated activity levels of several MMPs including MMP-3, MMP-8 and MMP-13

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Contraindication. Sensitivity to phosphate. Hypocalcaemia are present. For oral amino-bisphosphonates --> abnormalities of esophagus, which delay esophageal emptying such as stricture or achalasia, and inability to stand or sit upright for at least 30 minutes Drawbacks: Chronic administration over long periods to be effective. High cost Side effects: GI upset Esophageal ulcerations Chronic renal failure
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Bisphosphonates Bone resorption

Inactivation of basic multicellular units

Dental trauma Bone cellularity and blood flow Cell necrosis and apoptosis No tissue healing

Bisphosphonate associated osteonecrosis

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Animal studies with bisphosphonate use

Brunsvold et al. (1992) studied the Effects of bisphosphonate administration on clinical parameters and alveolar bone loss during ligature-induced experimental periodontitis in Monkeys with Systemic alendronate for 16 weeks
Significant reduction in bone density changes in the alendronate group compared with the placebo group.

Clinical parameters (PLI, GI, PPD) were not significantly affected by alendronate administration compared with placebo
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Bisphosphonates and Periodontal disease

Michael S. et.al 1995 studied Sixteen beagles with moderate-to-severe periodontitis for 6 months. GROUP1: received 3.0 mg/kg alendronate weekly orally GROUP2: received a placebo. Silk ligatures for the first 3 months to exacerbate the periodontal destruction. Clinical data attachment level, gingival index, plaque index, and mobility at baseline 1 month intervals.

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Intraoral radiographs at baseline, 3 and 6 months. The mandibles processed for histolology at 6th month RESULTS:

A statistically significant difference in bone mass

between the Alendronate and placebo groups.

Bisphosphonate : no effect on the clinical parameters

of gingival inflammation or plaque.
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Ouchi et al.(1998) studied the Effects of bisphosphonate administration on the progression of alveolar bone loss during ligature-induced experimental periodontitis in Beagle dogs with Systemic incadronate for 25 weeks. Incadronate administration prevented alveolar bone loss by reducing the increased alveolar bone turnover in dogs with experimental periodontitis
Alencar et al.(2002) studied the Effects of bisphosphonate administration on bone resorption during ligature-induced experimental periodontitis in Rats using Systemic clodronate for 11 days. Clodronate administration significantly reduced alveolar bone loss and inflammatory cell infiltrations compared with control animals
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Mitsuta et al.(2002) studied the Effects of bisphosphonate administration on alveolar bone resorption during ligature-induced experimental periodontitis in Rats with Topical clodronate for 7 days. Topical clodronate significantly reduced bone mineral density changes and the number of osteoclasts per alveolar bone surface compared with control animals Tani-Ishii et al. (2003) studied the Effects of bisphosphonate administration on the progression of Porphyromonas gingivalis-induced experimental periodontitis in Rat using Systemic incadronate for 8 weeks. Systemic incadronate significantly inhibited alveolar bone resorption and PMN migration compared with control animals
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Buduneli et al. (2004) studied the Effects of bisphosphonate administration on PGE2, PGF2a, and

LT-B4 levels and alveolar bone loss in endotoxin-induced

periodontitis in Rats with Systemic alendronate for 7 days. Significant reduction in the gingival tissue levels of PGE2 and LTB4 compared with control animals. No significant reduction in alveolar bone loss compared

with control animals

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Clinical studies on the effects of bisphosphonate administration

References Subjects Drug Pdtal Obser. Tmt period SRP 9 months Outcome

Jeffcoat & Reddy (1996)

40 with ChP

Systemic alendronate 10 mg/day for 6 months

Placebo group: 40% of sites lost bone height Test group: 20% of sites lost bone height Test group: 1.31.3 mm difference in bone height and 0.52 0.85mm CAL gain compared with placebo
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Rocha et al. (2001)

40 with ChP and Type 2 diabetes

Systemic alendronate 10 mg/day for 6 months

SRP

6 months

El-Shinnawi & El-Tantawy (2003)

24 with chronic periodontit is

Systemic alendronate 10 mg/day for 6 months

SRP

6 months

Significant difference (po0.001) in bone mineral density of maxilla and mandible . No significant difference in GI, PPD and CAL Ordinary dental treatment 45 years follow-up Improvements in clinical parameters (PPD and tooth mobility) and in alveolar bone density
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Takaishi et al. (2003)

4 women with chronic periodontit is

Systemic SRP etidronate 10 mg/day for 2 weeks at intervals of 6 months

INHIBIT BONE CALCIFICATI ON

CHANGE WBC COUNT

Osteonecrosis

Not approved for teatment of periodontal diseases

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Matrix Metalloproteinase Inhibitors

MMPs are a family of Zn+ and Ca+ dependent endopeptidases secreted or released by variety of inflammatory cells. Belong to a family proteolytic enzyme that degrades extracellular matrix molecules such as collagen, gelatin, and elastin..
At least 19 members.
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An imbalance between the activated MMPs and their inhibitors

pathological breakdown of the extracellular matrix in periodontitis.

Compensating for the deficit in the naturally accruing inhibitors or

TIMPs to block or retard the proteolytic destruction of connective tissue is of therapeutic significance.
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This can be accomplished with the use of drugs that can

1. Inhibit the synthesis and or release of these enzymes 2. Block the activation of precursor (latent) form of their MMPS (pro-matrix metalloprotienases). 3. Inhibit the activity of mature MMPs.

4. Stimulate the synthesis endogenous TIMPs or Protect the

hosts endogenous inhibitors from proteolytic inactivation

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The tetracycline, which may modulate many of these

matrix protective mechanisms, have been found to be

effective of MMPs mediated connective tissue destruction

in variety of pathological processes.

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MMP inhibitors

Endogenous TIMPs

2- macroglobulins

Exogenous

Zn+ and Ca2+ chelating agents Synthetic peptides Tetracyclines Bisphosphonates

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Enodogenius agents
Both bind in a non-covalent fashion to member of MMP

family.
TIMPs :control MMP activities pericellularly, secreted by various cells found in serum and human saliva, present high concentration in healthy sites. 2- macroglobulin functions as a regulation of MMPs in

body fluids. During inflammation, the high molecular wt.

protein may escape the vasculature and also function in the extracellular matrix.
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TIMPs:
Form high affinity, essentially irreversible non-covalent complex with the active form of MMPs. TIMP-1: - 30 KDa glycoprotein, synthesized and secreted by most connective tissue and macrophages. It binds to pro-gelatinase-B. TIMP2: - 21 KDa unglycolated proteins have 40% sequence identity with human TIMP 1. It binds to the proform of gelatinase A and involved in de activation.

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TIMP -3- Isolated from chicken cells and cloned from human and mouse sources. It almost exclusively bonds to extracellular matrix. TIMP 4: - recently isolated. TIMP4 has been shown to interact with MMP2

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B. Exogenous (Synthetic) Inhibitors: 1. Zn+ and Ca2+ chelating agents E.g. EDTA and 1, 10-phenananthrolin :are potent inhibitors of enzyme activity in vitro. Disadvantage toxic are not used as therapeutic agents 2) Synthetic peptides- as specific chelators: Phosphorus Containing Peptides E.g. Phosphonamidate, Phosphinate analog of tripeptides (Inhibits human skin fibroblast collagenase in vitro). -Substitues carbon atom with phosphorous atom in peptide substrate Sulphur based inhibitors e.g. Mercaptan derivatives: potent inhibitor of collagenase, gelatinase and stromelysins.
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Peptidyl hydroxamic acid derivatives:

Prepared by adding hydroxamic acid residues at C terminus of peptides as metal chelating moiety, which chelates Zn and inhibits MMP 1,2,3,7,8 & 9 in vitro. E.g.: Galardin -for non healing corneal ulcer Bitimastat -Parentral for breast cancer. Marimastat- Oral- for carcinomas Unfortunately because of insufficient specificity causes unwanted toxicity like joint pain & stiffness because of interaction with wrong MMPs
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Bisphosphonates: Not a specifically designed MMP inhibitor, but inhibits MMP 1,3,8 & 13 in vitro by cation chelation. Phospholipase A2 inhobitors: Cranberry fraction

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Tetracycline analogues
These are the only MMP inhibiters approved by FDA.

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Matrix metalloproteinase inhibition by tetracycline analogues: Multiple mechanisms

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A. Mediated by extracellular mechanisms:

1. Direct inhibition of active MMPs: dependent on Ca2+ and Zn2+ binding properties of tetracycline. This proposed mechanism has been supported by the following observations:

Adding excess Ca++ or excess Zn eliminated the ability of the TC analogues to inhibit collagenase activity in vitro; (Golub et. al 83) Structural evaluation of collagenase andTetracyclines such as doxycycline :it blocks the MMPs in vitro apparently by non-competitive inhibition (Stetler Stevenson et al.76).

These ndings suggest that the tetracyclines(except for cmt-5) may bind to the secondary Zn2+ (and to a lesser extent,Ca2+) in collagenase, thus altering the conformation of the enzyme molecule and blocking its catalytic activity in the extracellular ma-trix. 57

2.Action independent of cation binding property

pro-MMP

OXYDATIVE ACTIVATION

MMP

TETRACYCLINE-scavenge reactive oxygen species

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Indirect action:
.

1- antitrypsin

MMP

Serine proteinases

Tetracycline
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B. Mediated by cellular regulation :

1. Tetracycline decreases cytokines a) Inhibits activation of pro TNF- (Shapira et. al 1996) b) Inhibits IL- 1 (Golub et. al 98)

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CHEMICALLY MODIFIED TETRACYCLINE

Golub et al. (87) described first chemically modified tetracycline (4dedimethylamino tetracycline CMT-1):devoid of antibacterial activity (removal of the dimethylamino group from the carbon-4 position of the A ring of the drug molecule) but which retains anticollagenase activity A series of 10 different chemically modified tetracycines 110 fprmed Nine of which were found to retain their anti-collagenase but to have lost their antimicrobial properties.

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CMT lost its anti-collagenase property was CMT- 5, or the

pyrazole analogue, in which the C-11 carbonyl oxygen and

C-12 hydroxyl groups on Ring-B were replaced by nitrogen

atoms, which eliminated this important Zn or Ca binding site

on the tetracycline molecule.

CMT-1 (4-dimethlyamino tetracycline) dimethylamino group removed from the carbon 4 portion of the A-ring.
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CMT-2 or tetracyclinonitrile was produced by dehydration of the carboxamide residue at carbon 2.

CMT-3 - produced by removing the hydroxyl & methyl groups on carbon 6 & 4.

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CMT 4 (7-Chloro 4 dedimethylamino tetracycline) CMT 7 (12a-deoxy-4-dedimethyl amino tetracycline) CMT 8 (4 dedimethyl doxycycline).

In gnotobiotic rat model infected with the human

periodontopathogen, P. gingivalis showed reduced tissue

breakdown after daily oral administration CMT 1 over an

extended period (Golub et al 1991, 92)
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ANTICOLLAGENASE THERAPY: A potential adjunct in the management of the periodontal patient:

Three different animal models of periodontal disease have been used to examine the therapeutic potential of this newly discovered property of tetracyclines. Experiment 1: Surgically desalivated rats exhibit increased alveolar bone loss, and the daily oral administration of a sixth chemically modified tetracycline (4-hydroxy-4-dedimethylaminotetracycline) significantly ameliorated this tissue breakdown.

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Experiment 2:
McNamara et al.1990 induced diabetes & exposed ODU (Osaka Dental University) rats to several Periodonto-pathogens (P.gingivalis,

Fusobacterium spp., A.a)

He repeatedly gave increasing concentrations of doxycycline in vitro & found that the MIC of these organisms to the drug was increased. But, repeated exposure to CMT-1 did not significantly affect the MIC but can inhibit pathologically excessive collagen breakdown in periodontal diseases .
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Experiment - 3
Adult male Sprague-Dawley rats were monoinfected with P. gingivalis & it dramatically increased both gingival collagenase activity and alveolar bone loss compared with the uninfected controls. (Chang et al. ) Once again, the oral administration of doxycycline or CMT-1 sharply reduced collagenase activity and bone loss, even though the latter tetracycline compound is not an effective antimicrobial.
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Mechanism of action
CMTs have been shown to downregulate expression of gelatinases, & thus to reduce the production of pro-enzyme (MMP-2 and MMP-9) (Golub et al., 1991, 1998). Also, CMTs may inhibit the activation of collagenases (MMP-1, MMP-8, and MMP-13), and Inhibit Stromelysins (MMP-3, MMP-10,and MMP-11) and
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CMT effects on pro- collagenase activation:

PMNs

Osteoblasts
Secretes

Procollagenase
Activated ROS e.g. HOCL by neutrophils

Collagenase
Inhibits 40 80%

CMT-1
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Other mechanisms that have been proposed include: Inhibition of oxidative activation and increase in degradation of proMMP's, Inhibition of cytokine production, i.e., of TNF-alpha and IL-8, and Reduction of the expression of serine proteinase and trypsinogen-2. (Pruzanski et al., 1998; Kirkwood et al., 1999). Inhibition of non-collagenolytic proteases. Inhibit secretion of other collagenolytic enzymes like Lysosomal cathepsin.
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Effects on Osteoclast function

Inhibit gelatinase activity Diminish acid production

Inhibit its development

Diminish cathepsin secretion

Induce Osteoclast apoptosis

Alter Intracellular Ca+2

Decrease ruffled border
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Inhibit the net accumulation of PGE2:

CMT-3 has been shown to inhibit the net accumulation of PGE2 in endotoxin-stimulated murine macrophage models at a conc. of 10g/ml in tumor invasions. (Tsuiji et al., & Boolbol et al., 1997). CMT-3 does not inhibit COX-1 expression at the protein level, nor does it degrade the COX-1 protein or inhibit COX-1 specific activity in cell-free extracts. It has been speculated that this additional anti-COX-2 effect should be explored in various pathological conditions, including periodontitis, arthritis, and scleroderma, where TC therapy has been recommended.
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NO is known to inhibit the synthesis of matrix constituents such as collagen and proteoglycans, as well as upregulate MMP expression. A series of CMTs exhibited the following efficacy as NOS inhibitors: CMT-3 and CMT-8 > CMT-1 and CMT-2 > CMT-5 (the latter exhibiting no inhibitory activity) (Trachtman et al., 1996; Amin et aL, 1997).
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These data suggested that the relative potency of these compounds as inhibitors of NO production was positively correlated to their ability to function as MMP blockers.

Mechanism:
The suppression of NO synthesis by CMTs was found to be associated with reductions in iNOS expression apparently reflecting enhanced degradation of this enzyme's mRNA (Amin et aL, 1997).

The response of NOS to TCs provides an additional host-modulating nonantimicrobial therapeutic rationale for this family of drugs.
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Bone resorption Inhibition: As examples of in vitro efficacy, TCs and CMTs were found to inhibit bone resorption in both organ and cell culture, regardless of whether the resorption was induced by parathyroid hormone (PTH), PGE2, or bacterial endotoxin (Golub et al, 1984; Gomes et al, 1984; Rifkin et al, 1994). CMT-1 and -3 and CMTs-6, -7, and -8 were effective inhibitors of bone resorption in culture (CMT-8 was the single most potent compound), whereas CMT-2, -4, and -5 were not.
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Action on P.gingivalis & T.denticola:

Inhibits Arg- & Lys- gingipain activities & Collagenolytic activity of P.gingivalis. Inhibited trypsin like activity of T.denticola. CMT-I inhibited serum albumin degradation by P.gingivalis & T.denticola. CMT-1 inhibited the inactivation of 1 proteinase inhibitor by P.gingivalis.

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Synergistic Actions:
Greenwald et al.' recently conducted a synergism study using CMT-1 + flurbiprofen, a standard nonsteroidal anti-inflammatory drug selected primarily because of its reported beneficial effect on bone loss in humans with adult periodontitis and the beagle dog model of periodontal disease.

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CMTs potential advantages over conventional Tetracyclines: CMT-1 is absorbed after oral administration more rapidly and has a longer serum half life than tetracycline(observations in rats) Their long-term systemic administration does not result in gastrointestinal toxicity, No resistance.

Can be used for prolonged periods.

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Current status of CMTs:

CMTs have not yet been approved for human use by the FDA, although the

National Cancer Institute has recently initiated preliminary studies, using CMT-3,
on humans with cancer.

More recent studies have demonstrated the therapeutic potential of TCs' antiMMP activity in in vivo and cell culture models of cancer invasion, metastasis, and angiogenesis ( Masumori et al, Lokeshwar et al, Seftor et al.)

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SUBANTIMICROBIAL DOSE DOXYCYCLINE (SDD)

Doxycycline Hyclate (Periostat):- Available as 20-mg capsule, prescribed twice daily for use. Approved by U.S Food and Drug Administrator for the adjunctive treatment of periodontitis. It acts by suppression of the activity of colleginase, particularly that produced by PMNs. Can effectively lower MMP level.
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Evidence indicates that SDD regimens can

1) Inhibit the pathologically elevated collagenase actively in the gingival tissues &in the GCF of periodontitis patients. 2) Reduce the typical side effect produced by commercial available dose regimens of tetracyclines presumably because the peaks or maximum serum levels is reduced by about 90% compared to regular dose doxycycline regimens.
83

3) Prevent the progression of periodontitis: assessed

by measuring attachment loss. -Long term (i.e. 9-18 months) administration of SDD does not result in emergence of resistant organism or alteration of subgingival microflora.

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Caton et al (2000) in 190 adult patients using 20 mg bid for 9 months + SRP showed significant improvements in CAL ( 2mm) PD and BOP when compared to placebo group receiving only SRP. Golub et al (2001) in 51 patients with active periodontitis based on pocket depth and increased collagenase at multiple exams using doxycycline 20 mg bid show no clinical attachment loss over 36 months.

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Preshaw et al (2002) used doxy 20-mg bid for month and SRP in 208 chronic periodontitis subjects showed improvements in clinical

attachments level and PD 4 mm

Novak et al (2002) in 20 subjects 45 yr. old patients with severe gen. periodontitis patients showing > 30% of sites with CAL 5 mm used doxycycline for 6 months. The result showed less CA loss and PD, GI and BOP when compared to placebo (not significant).

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Contents
Introduction Risk factors Perioceutics Historical perspectives Host modulation Host modulation options Classifications of agents Host modulation agents Whom to treat with HMT? Conclusion References
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[II] Modulation of host inflammatory mediators

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MODULATION OF ARACHIDONIC ACID METABOLISM

Arachidonic acid:a 20-carbon eicosanoid, is liberated from
plasma membrane phospholipids via the enzyme,

phospholipase A2
Free arachidonic acid can then be metabolized via

cyclooxygenase or lipoxygenase enzyme pathways.

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92

Cox-1 enzyme expressed constitutively in most tissue.

Cox-2 inducible

involved in inflammation cellular differentiation mitogenesis.

Collectively implicated in a wide range of events associated with

disease, such as platelet aggregation vasodilatation and neutrophil chemotaxis and increase vascular permeability.
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AA metabolites mediators of tissue destruction in inflammatory diseases -including periodontal diseases. The majority of NSAIDs are weak organic acids inhibit selectively (COX-2) and non-selectively (COX-1) inhibit the synthesis of AA metabolites blocks the production

94

Role of arachidonic acid metabolites in disease

Goldhaber et al. (73) observed that NSAID, indomethacin, inhibited up to 90% in vitro bone resorption.

Indirect evidence that arachidonic acid metabolites were

responsible for a large portion of the enhanced in vitro osteoclastic activity.
95

Goodson et al. (74) demonstrated that solutions containing prostaglandin E2 injected subcutaneously over the calvaria of adult rats stimulated rapid in vivo resorption of bone.

Goodson et al. (74) found a ten-fold elevation in prostaglandin

E2 in periodontally diseased tissue as compared with healthy tissue.
96

Offenbacher et al. (86) monitored periodontal status and

crevicular prostaglandin E2 levels in adult periodontitis patients over an 18- to 36-month period.

Mean GCF prostaglandin E2 concentrations : elevated in the

patients with periodontal attachment loss compared to healthy patients.
97

Nyman et al. : investigated the modulation of arachidonic acid metabolites with systemic indomethacin

Documented : systemic doses of the NSAID suppressed

alveolar bone resorption and gingival inflammation.

98

Studies on modulation of A.A derivatives

(1979)

(1981)

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100

101

102

months

months

103

104

105

106

Selective cyclooxygenase 2 inhibitors such as meloxicam, nimesulide, etodolac and celecoxib have potencies for cyclooxygenase 2 that are 10- to 1000-fold higher than for

cyclooxygenase 1.
Have fewer side effects - Lower gastric ulcer, lower bleeding tissue. NSAID:not approved by FDA
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Pro- resolution agents

108

Serhan et al. (97) have recently described a novel series of oxygenated arachidonic acid derivatives called lipoxygenase interaction products or lipoxins which appear to function as endogenous anti-inflammatory mediators.

109

These derivatives (such as lipoxin A and lipoxin B) arise

via 15- or 5-lipoxygenase activities and by cell-to-cell

inter-actions and appear to serve as endogenous antiinflammatory mediators.

110

Serhan et al 95 have demonstrated that aspirin triggers cellular

synthesis of lipoxins as part of its beneficial actions.

Inhibit polymorpho nuclear leukocyte adhesion. Stimulate vasodilatation Block some of the pro-inammatory effects of leukotrienes

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Although neither of these agent classes has been therapeutically tested extensiveley in animals or humans with periodontal disease, they may logically present with reduced side effects or enhanced efficacy as compared with current NSAIDs.

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LxA4 and its analogs, 1. Modulates IL-8 release at the gene transcriptional level 2. Suppress TNF- ,macrophage inflammatory peptide 2 and IL - 1 3. Enhance phagocytosis of apoptotic PMN by monocyte derived macrophages. .

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LXA4 and LXB4:acts on monocyte, stimulates

chemotaxis and adherence. These cells do not degranulate or release reactive oxygen species in response to lipoxins

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Monocyte activities may be host protective as these cells are

involved in wound healing and resolution of inflammatory sites.

In a mouse model, it was shown that administration of

metabolically stable analogues of lipoxins (LxA4) blocked

P.gingivalis elicited neutrophils and also reduced PGE2 levels.

(Pouliot M et al 2000).

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Resolvins
Resolvins, a new family of biologically active products of omega-3 fatty acids, have the therapeutic potential to resolve periodontal inflammation and restore the gums to health. EPA : Resolvins of the E series (RvE1) DHA :Resolvins of the D series (RvD).
116

RvE1promotes resolution of inammation through direct limitation of PGE2 and cytokine secretion(solid red arrow). Indirect effects include blocking of osteoclast formation and secretion of antibacterial peptides by resident cells(open red arrows)
117

The local resolvin E1 (RvE1) application on experimental periodontitis in rabbits was experimented on. The results showed that compound has efficacy on preventing P. gingivalis induced periodontal disease and bone resorption.

In a rabbit model of human periodontal disease, local application of RvD1 in small amounts (4g/site) :complete resolution of inflammation and regeneration of bone.(H. HASTURK et al 2009)
118

Option 3: Block Major Regulators of Host Defenses

Although many host mechanisms are involved in control
of the bacterial challenge, the most important mechanisms in periodontal diseases appear to be PMNs and antibody A variety of host mediators regulate antibody level and PMN function.

Further studies needed

119

PGE2 ,IL-1,TNF-a,and active oxygen species at various

levels ,may enhance or disrupt defense mechanisms.

Some cytokines such asIL-4 and IL-10 are primarily anti

inammatory and serve to control tissue distruction.

120

Regulating Cytokines
Cytokines are defined as regulatory proteins controlling the survival, growth, differentiation and functions of cells. They are produced transiently at lower concentration and

act on responding cells that are usually present nearby.

Later the responding cells destroys these cytokines by receptor mediated endocytosis.

121

They function as network, are produced by different cell

types and share overlapping features. This phenomenon is

called BIOLOGICAL REDUNDANCY.

Constituents of the plaque biofilm stimulate host cells

produce proinflammatory cytokines ( IL-1,TNF-

etc) induces connective tissue & alveolar bone destruction.
122

These cytokines are present in diseased periodontal tissues and Gingival Crevicular Fluid (GCF) (Gemmell et al, 1997). Catabolic activities of cytokines controlled by endogenous inhibitors like IL-1 and TNF- receptor antagonists

123

When administered for therapeutic purposes, these antagonists can reduce inflammation. The use of cytokine receptor antagonists to inhibit

periodontal disease progression has been investigated in a

ligature-induced periodontitis non-human primate model.

124

It was demonstrated that IL-1/ TNF- blockers partially

inhibited disease progression.

However, the use of cytokine antagonists to treat human

periodontal disease needs to be evaluated (Delima et al,

2001).
Cytokines implicated in suppression of the destructive

inflammatory response include IL-4, IL-10, IL-11 and

TGF-.
125

Both IL-4 and IL-10 can target macrophages and inhibit the release of IL-1, TNF-, reactive oxygen intermediates and NO. IL-4 induce programmed cell death (apoptosis) which reduced the number of inflammatory macrophages. It can also upregulate the production of IL-1 receptor antagonists (Wong et al, 1993).
126

Recently, recombinant human IL-11, which inhibits productions of TNF-alpha,IL-1 and NO, are also shown to reduce disease progression in a ligature-induced periodontitis canine model (Martuscelli et al, 2000).

127

The evidence that IL-4 is deficient in diseased periodontal tissues, and the finding of exogenous IL-4 administration in experimental arthritis which reduces inflammation, suggested that the use of this cytokine may provide a therapeutic benefit in the treatment of periodontal diseases

128

Currently, anticytokine therapy using anti-IL-1 or anti-tumor necrosis factor- monoclonal antibodies and soluble TNF- receptors have been approved for the treatment of rheumatoid arthritis, Crohns disease, juvenile arthritis and psoriatic arthritis with research continuing on periodontal disease.

129

IL-1 and TNF antagonists

Reduced the loss of connective tissue attachment and the loss of alveolar bone height Progression of periodontal disease can be retarded by antagonists to specific host mediators

Demonstrating s IL-1 and tumor necrosis factor inhibitors may provide a potential treatment modality to combat the disease process. (Delima et al.2001)
130

Ligature-induced periodontitis in monkeys

Reduced histologic levels of osteoclasts and bone loss

These studies suggest that the conversion from gingivitis to periodontitis is directly associated with the movement of an inflammatory infiltrate toward alveolar bone, and that this activity is at least partially dependent upon IL-1and /or tumor necrosis

factor

131

Spirinolactone (Aldrogen Kentarci- 2006)

Aldosterone inhibitor:has anti-TNF alpha activity Animal study didnt show positive result:may be due
to fast metabolism of drug, incomplete inhibition of TNF alpha

Cranberry fraction(Bodet 2007)

LPS induced IL-6,8.PGE2 responses of gingival

fibroblast :inhibited

Inhibit fibroblast intracellular signalling protein Reduce cox-2 expression

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Omega 3 fatty acid

Rat fed on fish oil for 22 weeks
Infected with Pg

Rat fed on corn oil for 22 weeks

Infected with Pg

Killed and analysed for TNF

lpha,IL 1 beta

Killed and analysed for TNF

lpha, IL 1 beta

Decrease in IL1beta,TNF-alpha in rat fed on omega3 fatty

acid than corn oil,and decrease in bone resorption

detected(Kesavalu-2007)
133

Pentoxifylline
Pentoxifylline (PTX), a methylxanthine derivative,

specially blocks the synthesis of TNF-, among other

cytokines, by inhibiting gene transcription, thereby reducing the accumulation of TNF- mRNA. The protective effect of PTX could be explained by its capacity to inhibit the production of inflammatory

cytokines or to stimulate anti-inflammatory cytokine

production
134

Thalidomide
Thalidomide was shown to inhibit TNF- production by enhancing the degradation of its messenger RNA without affecting the production of either IL-1 or IL-6 . Patient with erythema nodose of leprae, HIV, multiple myeloma or tuberculosis under TLD treatment displayed a reduction in clinical symptoms correlating with TNF- serum levels.
135

Anakinra (Kineret)
It is an interleukin-1 (IL-1) receptor antagonist. It competitively inhibits the binding of IL-1 to the Interleukin-1 type receptor.[Dashash Met al 2004] Anakinra blocks the biological activity of naturally occurring IL-1, including inflammation and cartilage degradation
136

Dosage is 100mg subcutaneously once daily Potential Side Effects injection site reactions infections and neutropenia malignancy immunogenecity

137

IL-4
Reduce the activity of AA pathway.
Reduces cytokine & enzyme production Stimulate apoptosis in-vitro

Up-regulates the production of IL-1 receptor antagonist.

138

IL-10
Inhibits the antigen presenting capacity of macrophages Decreases proliferation and production of cytokines by activating T-cells. Suppress macrophages function & IL-12 production Inhibit macrophage derived IL-1, 6, 8

Enhances IL-ra productions

Enhances B-cell proliferation & differentiation
139

In conclusion, despite expanding use of drugs blocking

proinflammatory cytokine production their precise mechanisms

of action remain unclear.

Early assumptions that they act by direct neutralization of the

toxic inflammatory effects of tumor necrosis factor- might be

too simplistic, because they cannot explain the range of effects

observed or the varying properties of different tumor necrosis

factor-blocking agents.
140

However, unresolved issues regarding cytokine

modulation therapy included, identifying the ideal method

to maintain or inhibit cytokines long term, and

understanding the systemic implications associated with

altering cytokine levels on tissue homeostasis

141

Therefore, additional animal and human studies are needed

to determine the safety and efficacy of anti-inflammatory

cytokines in the treatment of periodontitis.

142

REGULATING REACTIVE OXYGEN SPECIES

These are molecules or molecular fragments that contain one

or more unpaired electrons in their outer orbits.

Oxygen Derived Free Radicals (ODFR) such as superoxide and hydroxyl radicals are integral products of normal cellular metabolism. In addition other components of oxygen metabolism include Hypochlorous acid (HOCl).
143

Increased in inflammation &tissues may be exposed to free radicals where there is abundance of Polymorphonuclear neutrophils and macrophages. HOCl act on the tissues through collagenase and gelatinase. They cause depolymerization of collagen, hyaluronan and proteoglycan which are normally neutralized by antioxidants
144

For example, Nitric Oxide (NO) is a free radical involved in

host defense that can be toxic when present at high levels and it has been implicated in a variety of inflammatory conditions.

It is synthesized invivo from the substrate L-arginine by 3

isoenzymes called NO synthases, NOS1, NOS2 & NOS3.

NOS1 & NOS3 are constitutively secreted from neuronal and endothelial cells respectively.
145

NOS2 is an inducible form (iNOS) that is produced at

higher concentrations in response to inflammatory stimuli (Trachtman et al 1996 They cause,
lipid peroxydation protein and DNA damage stimulation of cytokine release.
146

Inhibitor of iNOS
Merkaptoalkyguanides are inhibitors of iNOS : are found to decrease inflammation in animal models. They are found to, block iNOS

inhibit COX
Benedek et al (1998) demonstrated in a ligature-induced

periodontitis rat model, that an NO inhibitor

(mercaptoethylguanidine) resulted in decreased bone loss.
147

Grape seed proanthocyanidins

Reported to possess a wide range of biologic properties against oxidative stress. In a study, authors investigated the effects of a grape seed proanthocyanidin extract (GSE) and commercial polyphenols on the production of ROS and RNS and on the protein expression of inducible nitric oxide synthase (iNOS) by murine macrophages stimulated with lipopolysaccharides (LPS) of periodontopathogens.
148

GSE strongly decreased NO and ROS production and

iNOS expression by LPS-stimulated macrophages.

GSE :strong inhibitory effect on NO production without

affecting iNOS expression but slightly increasing ROS production. The findings demonstrate that proanthocyanidins have potent antioxidant properties and should be considered a potential agent in the prevention of periodontal diseases. 149

Possible strategies in the future

Tranilast A recent study showed :the effect of tranilast, which suppresses collagen synthesis and cell proliferation, on matrix metalloproteinase- 1 secretion from human gingival fibroblasts, did not interfere with cell proliferation at low concentrations. Higher doses of tranilast significantly decreased the activity of matrix metalloproteinase by 130%

Data suggest that tranilast up-regulates the expression of

type 1 collagenase suppressed by gingival overgrowth-

inducing drugs, and inhibits transforming growth factor-b

secretion from gingival fibroblasts at lower doses

151

Potassium channel blockers Therapies aimed at decreasing the expression of RANKL and pro-inflammatory cytokines by T-cells constitutes a

promising strategy to ameliorate bone resorption and

inflammation.

The potassium channels Kv1.3 and IKCa1, through the use of selective blockers, play important roles in T-cell-

mediated events, including T-cell proliferation and the

production of pro-inflammatory cytokines.
152

A potassium channel-blocker for Kv1.3 has been shown to

down-regulate bone resorption by decreasing the ratio of

RANKL-to- OPG expression by memory-activated T-

cells(Valvare-2005)

153

Xylitol
Widely believed to possess anticaries properties.

To date, little is known about the effect of xylitol on

periodontitis.

A study was carried out to determine tumor necrosis factor

alpha and interleukin-1 expression when RAW 264.7 cells were stimulated with P. gingivalis LPS and the effect of xylitol on the LPS-induced TNF- and IL-1 expression.154

Pretreatment with xylitol inhibited LPS-induced TNF-

and IL-1 gene expression and protein synthesis. Showed inhibitory effect on the growth of P. gingivalis.

Xylitol may have good clinical effect not only for caries
but also for periodontitis.

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Tacrolimus
Since Tacrolimus, is an immunomodulatory drug used for the treatment of some cases of arthritis, it is hypothesized that it may modulate periodontal disease. In murine model of ligature-induced periodontal disease,

assessed the effects of daily administrations of Tacrolimus

(1 mg/kg body weight) on bone loss, enzymatic (myeloperoxidase) analysis, differential white blood cells

counts, and cytokine expression for 530 days.

156

Radiographic, enzymatic (myeloperoxidase) and

histological analysis revealed that Tacrolimus reduced the

severity of periodontitis

157

Recombinant human interleukin11 (rhIL-11)

Interleukin 11 has been shown to have anti-inflammatory
effects by inhibition of TNF- and other proinflammatory cytokines. IL-11 directly minimizes tissue injury through the stimulation of a tissue inhibitor of metalloproteinases-1

(TIMP-1

158

Martuscelli et al. carried out a study using recombinant

human interleukin-11 (rhIL-11) in the treatment of

ligature-induced periodontitis, in dogs.

Significant reduction in the rate of clinical attachment loss

and radiographic bone loss after an eight-week period of rhIL-11 administration, twice a week
159

WHOM TO TREAT WITH HMT?

On the basis of available data, it seems reasonable to

conclude that the immunoinflamatory response is

sufficienly protective in most individuals such that

minimal periodontal destruction will occur with routine

oral hygiene.
160

But in individuals who exhibit severe generalized periodontitis with excessive immunoinflammatory response, host modulation with bacterial control seems to be an appropriate therapeutic strategy. Those include patients with diabetes, composite genotype, smoking, osteoporosis, stress, estrogen depletion, institutionalized geriatric patients etc.,

161

It becomes apparent that the use of systemic host modulatory therapy by the dentist may not only improve patients periodontal condition but also provide systemic benefits for other inflammatory disorders with related tissue destruction such as arthritis, CVD, dermatological conditions, diabetes, osteoporosis and so forth.

162

CONCLUSION
It is likely that management of disease or prevention of disease in individuals with signicantly in-creased risk for periodontitis will require either extreme bacterial control or combinations of bacterial control plus host modulators.

Therapeutic agents that are directed at modulation of

various host mediators have shown signicant promise for the management of periodontitis. Recent enhancements to our understanding of the pathogenesis of periodontitis suggest host modulators together with control of the bacterial challenge will become a practical approach to the management of patients with an increased risk for periodontal disease
164

The proper management of periodontitis may prove to

have an impact on general health, making a significant

contribution to human welfare.

The adjunctive use of host modulatory therapy can enhance therapeutic responses ,slows progression of disease,allows more predictable management of patients, who are at increased risk to develop periodontal disease
165

Though various agents are suggested only SDD & TETRACYCLINE are FDA approved. Further studies are needed to substantiate the use of other agents.

166

REFERENCES
Clinical infectious disease 1999;28 Clinical periodontology :Carranza Perio2000 ;14 Perio2000;24 Perio2000;48 CID 1999;28 JOP 2000,71 JOP2003 JCP 2004;31 JDR 2005;84 JDR 2006;85Oral health and preventive dentistry 2009;7 IJPRD 2008 JISP2009;13(2) Internet sources
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