host modulation soorya

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HOST MODULATION

THERAPY

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Contents

IntroductionRisk factors

Perioceutics

Historical perspectives

Host modulationHost 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

Enzymes and cell wall components of bacteria:

destroy extracellular matrix

activate osteoclastic resorption of bone.

Direct Indirect

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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 :

Acquired

Genetic risk factors.

Environmental

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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.

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RISK FACTORS

The severity of periodontal diseases, its rate of progression andits 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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Tissue destruction

Interference

Host factor

Alter disease progression

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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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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 Non-

Steroidal Anti- Inflammatory Drug.

This finding also indirectly suggested : prostaglandins werekey players in the bone loss of periodontitis

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These investigators then examined the role ofProstaglandins 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 wereable 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,

Hostthe organism from which a parasite obtains its

nourishment / in the transplantation of tissue, the

individual who receives the graft.

Modulationthe 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 stabil ize the

per iodontium 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

periodontalbreakdown.

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Host immune

Inflammatory

response

Microbial

challange

Anti-cytokine drugs

Clinical signs

of disease

Mechanical treatment

Bisphosphonates

Antimicrobial adjuncts:local

Delivery drugsSDD CMTs

CT &bone

metabolism

Antibody

PMN

Antigens

LPS

Other

virulence

factors

Cytokines

Prostanoids

MMPs

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Classification of various host

modulation therapiesKenneth s kornman-1999

Host modulation 1: Block Direct Effectors of Bone and

Connective tissue DestructionEg :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 DestructionThe 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 ofosteoclastic bone destruction and destruction of connective

tissues by MMPs.

Bisphosphonates MMP inhibitors

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BISPHOSPHONATES:

Bisphosphonates : potent inhibitors of bone resorption byosteoclasts

Have an effect on osteoblasts.

Bisphosphonates are analogues of pyrophosphatea 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 inpreventing the dissolution ofhydroxyapatitehencearresting bone loss.

Actual mechanism of action demonstrated only in the1990s

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CHEMISTRY

Pyrophosphate is produced by manyanabolic processes.

It is rapidly hydrolyzed to its twoconstituent phosphate groups. If the

linking oxygen atom in the pyrophosphatemolecule is replaced by a carbon atom, a

bisphosphonate is formed.

These analogues are completely resistantto hydrolysis and are chemically extremelystable. Like pyrophosphate, they bind tothe hydroxyapatite crystals of bone and

prevent their dissolution.

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Classification1. Based on the generation:

First generation: with alkyl side chains

E.g., etidronate

Second-generation: amino-bisphosphonates withan 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 theNHANES 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 thanin 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 osteoclast-

mediated bone resorption in estrogen-deficient patients.

Peripheral blood monocytes from patients with osteoporosis secrete

more interieukin-1 (IL-1).26


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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

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Mecahnism of action

A. Direct action on osteoclasts:Bisphosphonate mediate inhibition of osteoclasts

Induction of osteoclastic apoptosis throughactivation of the capasase pathway.

Reduction of activity of osteoclasts

Prevention of development of osteoclasts fromhaematopoietic precursors

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B. Indirect actions:

1- hydroxyethylidene-1, 1-bisphosphonate (HEBP) hasosteostimulative properties both invitro and invivoHEBP mediated increases in matrix formation,,

increased mineralized bone formation.

HEBP treatment in vivo promotes osteoblasticdifferentiation in calvarial wounds, as well as a

reversible stimulation of alveolar and calvarial bonewidth and reversible reductions in periodontal ligamentspace width.

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Tissue Level Cellular Level

Bone turnover

Bone resorption

Number of new bonemulticellular units

Net positive whole

body bone balance

Osteoclast recruitment

Osteoclast apoptosis

Osteoclast adhesion

Release of cytokines by macrophages

Osteoblast differentiation and number

Bisphosphonate modulation of bone

metabolism:

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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 minutesDrawbacks:

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

Bone cellularity and blood flow

Cell necrosis and apoptosis

Bisphosphonate associated osteonecrosis

No tissue healing

Dental trauma

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Animal studies with bisphosphonate

useBrunsvold et al. (1992) studied the Effects of

bisphosphonate administration on clinical parameters andalveolar bone loss during ligature-induced experimental

periodontitis in Monkeys with Systemic alendronate for 16

weeks

Significant reduction in bone density changes in thealendronate group compared with the placebo group.

Clinical parameters (PLI, GI, PPD) were not significantlyaffected by alendronate administration compared with

placebo

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Michael S. et.al 1995 studied Sixteen beagles withmoderate-to-severe periodontitis for 6 months.

GROUP1: received 3.0 mg/kg alendronate weekly orally

GROUP2: received a placebo.

Silk ligaturesfor the first 3 months to exacerbate theperiodontal destruction.

Clinical dataattachment level, gingival index, plaque

index, and mobilityat baseline

1 month intervals.

Bisphosphonates and Periodontal disease

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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 ofbisphosphonate administration on the progression ofalveolar bone loss during ligature-inducedexperimental periodontitis in Beagle dogs withSystemic incadronate for 25 weeks. Incadronateadministration prevented alveolar bone loss byreducing the increased alveolar bone turnover in dogs

with experimental periodontitis

Alencar et al.(2002) studied the Effects ofbisphosphonate administration on bone resorption

during ligature-induced experimental periodontitis inRats using Systemic clodronate for 11 days. Clodronateadministration significantly reduced alveolar bone lossand inflammatory cell infiltrations compared withcontrol animals

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Mitsuta et al.(2002) studied the Effects ofbisphosphonate administration on alveolar bone

resorption during ligature-induced experimentalperiodontitis in Rats with Topical clodronate for 7 days.Topical clodronate significantly reduced bone mineraldensity changes and the number of osteoclasts peralveolar bone surface compared with control animals

Tani-Ishii et al. (2003) studied the Effects ofbisphosphonate administration on the progression ofPorphyromonas gingivalis-induced experimental

periodontitis in Rat using Systemic incadronate for 8weeks. Systemic incadronate significantly inhibitedalveolar bone resorption and PMN migration comparedwith 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 comparedwith control animals

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Clinical studies on the effects of bisphosphonate

administration

References Subjects Drug PdtalTmt Obser.period Outcome

Jeffcoat &

Reddy

(1996)

40 with ChP Systemic

alendronate

10 mg/day

for 6 months

SRP 9 months Placebo group: 40% of

sites lost bone

height

Test group: 20% ofsites lost bone

height

Rocha et al.

(2001)

40 with ChP

and Type 2

diabetes

Systemic

alendronate

10 mg/day

for 6 months

SRP 6 months Test group: 1.31.3

mm difference in

bone height and

0.52 0.85mm

CAL gain

compared with

placebo

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El-Shinnawi &

El-Tantawy

(2003)

24 with

chronic

periodontitis

Systemic

alendronate

10 mg/dayfor 6 months

SRP 6

months

Significant

difference (po0.001)

in bone mineraldensity of maxilla

and mandible . No

significant difference

in GI, PPD and CAL

Takaishi et al.

(2003)

4 women

with

chronic

periodontit

is

Systemic

etidronate 10

mg/day

for 2 weeks

at intervals of

6months

SRP Ordinary dental

treatment

45 years

follow-up

Improvements in

clinical parameters(PPD and tooth

mobility) and in

alveolar bone

density

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Not approved for teatment ofperiodontal diseases

Osteonecrosis

INHIBITBONE

CALCIFICATION

CHANGEWBC COUNT

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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

TIMPs

2- macroglobulins

Endogenous

Zn+ and Ca2+ chelatingagents

Synthetic peptides Tetracyclines

Bisphosphonates

Exogenous

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Enodogenius agentsBoth 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

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TIMPs:

Form high affinity, essentially irreversible non-covalent complexwith 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.

TIMP

2: - 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.

TIMP4: - 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 activityin vitro.

Disadvantage toxicare not used as therapeutic agents

2) Synthetic peptides- as specific chelators:

Phosphorus Containing Peptides

E.g. Phosphonamidate, Phosphinate analog of tripeptides (Inhibits human skinfibroblast collagenase in vitro).

-Substitues carbon atom with phosphorous atom in peptide substrate

Sulphur based inhibitors

e.g. Mercaptan derivatives: potent inhibitor of collagenase, gelatinase andstromelysins.

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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+ andZn2+ 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 findings 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


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pro-MMP

TETRACYCLINE-scavenge reactive oxygen species

MMPOXYDATIVE ACTIVATION

2.Action independent of cation binding property

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Indirect action:

.1- antitrypsin

Serine proteinases

MMP

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 (4-

dedimethylamino 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 anticollagenaseactivity

A series of 10 different chemically modified tetracycines 110

fprmed

Nine of which were found to retain their anti-collagenase but to havelost 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


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y p y

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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CMT4 (7-Chloro4 dedimethylamino tetracycline)

CMT7 (12a-deoxy-4-dedimethyl amino tetracycline)

CMT8 (4dedimethyl doxycycline).

In gnotobiotic rat model infected with the human

periodontopathogen, P. gingivalis showed reduced tissue

breakdown after daily oral administration CMT1 over an

extended period (Golub et al1991, 92)65


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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-de-

dimethylaminotetracycline) significantly ameliorated this tissue breakdown.

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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 .

Experiment 2:

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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.

Experiment - 3

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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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PMNs Osteoblasts

Procollagenase

Collagenase

ROS e.g. HOCL byneutrophils

Secretes

Activated

CMT-1

Inhibits 4080%

CMT effects on procollagenase activation:

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Oth h i th t h b d i l d


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Other mechanisms that have been proposed include:

Inhibition of oxidative activation and increase in degradation of pro-

MMP'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.72


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Effects on Osteoclast function

Diminish acidproduction

Diminish cathepsin

secretion

Inhibit gelatinaseactivity

Inhibit its

development

Induce Osteoclast

apoptosis Decrease ruffled

border

Alter Intracellular

Ca+2

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CMT-3 has been shown to inhibit the net accumulation ofPGE2 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 effectshould be explored in various pathological conditions, including

periodontitis, arthritis, and scleroderma, where TC therapy has

been recommended.

Inhibit the net accumulation of PGE2:

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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). 75

These data suggested that the relative potency of these compounds as inhibitors


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gg p y p

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 non-

antimicrobial therapeutic rationale for this family of drugs.

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Bone resorption Inhibition:


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Bone resorption Inhibition:

As examples ofin 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.77


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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 byP.gingivalis.

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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.

Synergistic Actions:

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CMT t ti l d t ti l T t li


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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 ofCMTs:

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' anti-

MMP activity in in vivo and cell culture models of cancer invasion, metastasis,

and angiogenesis ( Masumori et al, Lokeshwaret 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.

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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 periodontitisbased 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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88

C t t


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Contents

Introduction

Risk factors

Perioceutics


Host modulationHost modulation options

Classifications of agents

89

Host modulation agents

Whom to treat with HMT?Conclusion

References


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[II] Modulation of host inflammatory

mediators

90

MODULATION OF ARACHIDONIC


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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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Cox-1enzyme expressed constitutively in most tissue.

Cox-2inducible

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


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disease

Goldhaberet 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


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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


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Offenbacheret 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.

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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


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99

(1979)

(1981)


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103

months

months


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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

107

Pro- resolution agents


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Pro resolution agents

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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.

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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 anti-

inflammatory mediators.

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S h t l 95 h d t t d th t i i t i ll l


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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-inflammatory 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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M t ti iti b h t t ti th ll


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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).

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117

RvE1promotes resolution ofinflammation 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)


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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 ofRvD1 in small amounts (4g/site) :complete

resolution of inflammation and regeneration of bone.(H.

HASTURK et al 2009)

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Option 3: Block Major Regulators of
mailto:[email protected]:[email protected]:[email protected]:[email protected]


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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

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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

inflammatory and serve to control tissue distruction.

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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


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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.

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These cytokines are present in diseased periodontal tissues

and Gingival Crevicular Fluid (GCF) (Gemmell et al,

1997).

Catabolic activities of cytokinescontrolled by

endogenous inhibitors like IL-1 and TNF- receptor

antagonists

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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


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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


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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).

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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).

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Th id h IL 4 i d fi i i di d i d l


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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

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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.

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IL-1 and TNF antagonists


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Demonstrating s IL-1 and tumor necrosis factor inhibitors

may provide a potential treatment modality to combat the

disease process. (Delima et al.2001)

IL 1 and TNF antagonists

Reduced the loss ofconnective tissueattachment and the loss ofalveolar bone height

Progression of periodontaldisease can be retarded byantagonists to specific hostmediators

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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

Ligature-induced periodontitis

in monkeys

Reduced histologic levels of

osteoclasts and bone loss

131

Spirinolactone (Aldrogen Kentarci- 2006)


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Aldosterone inhibitor:has anti-TNF alpha activity

Animal study didnt show positive result:may be due

tofast 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 132

Omega 3 fatty acid


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Rat fed on fish oil for 22

weeks

Infected with Pg

Killed and analysed for TNF

lpha,IL 1 beta

Rat fed on corn oil for 22

weeks

Infected with Pg

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


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y

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

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Thalidomide


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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

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Anakinra (Kineret)


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( )

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

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Dosage is 100mg subcutaneously once daily

Potential Side Effects

injection site reactions

infections and neutropeniamalignancy

immunogenecity

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http://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.htmlhttp://www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/il1.html


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Reduce the activity of AA pathway.

Reduces cytokine & enzyme production

Stimulate apoptosis in-vitro

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

IL-4

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IL-10


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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


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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.

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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

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Therefore, additional animal and human studies are needed

to determine the safety and efficacy of anti-inflammatory

cytokines in the treatment of periodontitis.

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REGULATING REACTIVE OXYGEN SPECIES


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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


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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 anti-

oxidants 144

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


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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.

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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

I nhibitor of iNOS


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Merkaptoalkyguanidesare 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


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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


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g y p

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 futureTranilast


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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%


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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


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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.

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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)

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Xylitol


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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-


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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.

155

TacrolimusSince Tacrolimus is an immunomodulatory drug used for


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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.

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Radiographic, enzymatic (myeloperoxidase) and

histological analysis revealed that Tacrolimus reduced the

severity of periodontitis

157

Recombinant human interleukin-

11 ( h 11)


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11 (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

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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

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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


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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


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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


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It is likely that management of disease or prevention of disease in

individuals with significantly 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


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various host mediators have shown significant 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


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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

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Though various agents are suggested only SDD &

TETRACYCLINE are FDA approved.

Further studies are needed to substantiate the use of other

agents.

166

REFERENCES


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Clinical infectious disease

1999;28

Clinical periodontology

:CarranzaPerio2000 ;14

Perio2000;24

Perio2000;48CID 1999;28

JOP 2000,71

JOP2003

JCP 2004;31

JDR 2005;84

JDR 2006;85Oral health

and preventive dentistry

2009;7

IJPRD 2008JISP2009;13(2)

Internet sources167


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host modulation soorya

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