PeriodontalSystemic Interrelationships

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Periodontal-Systemic Interrelationships

• Antonio J. Moretti, DDS, MS
• The University of Texas Houston Health Science
  Center Dental Branch

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Periodontal Diseases and Systemic Diseases

• A two-way street
• Is the old focal infection theory rearing its
  head?
• Are we getting closer to become true oral
  physicians?

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Periodontal Diseases and Systemic Diseases

• Dentists need to know more about systemic
  diseases and physicians need to increase their
  knowledge of oral diseases

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Periodontal Disease

• 10 to 15 of US adults have severe periodontal
  disease
• The same is true for the rest of the world
• Factors other than chance or poor dental habits
  predispose people to periodontal disease

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Roy Page,1998
Moderate to Severe Periodontitis with at least 28
teeth present
72 cm2 of pocket epithelium in contact with
biofilms
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Systemic conditions as risk factors for
periodontal disease

• Diabetes
• Smoking
• HIV
• Osteoporosis
• Menopause
• Angst-Related Psychosocial Factors

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Diabetes - short review

• IDDM (type 1)
• 5 to 15 of cases. Abrupt onset, commonly at
  puberty
• Destruction of insulin production beta cells in
  the pancreas via autoimmune process
• NIDDM (type 2)
• 2 to 3 of population. Recognized only 50 of
  cases
• Reduced insulin production
• Control with diet, hypoglycemic drugs, or
  combination

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Diabetes Mellitus - Hypothesis

• Hyperglycemia produces oxidation of protein and
  lipids. This will result in advanced glycation
  end products (AGE)
• AGEs are primarily responsible for collagen
  cross-links leading to macrovascular
  complications (hardening of arteries)
• AGEs bind to endothelial cells and macrophages
• Macrophages that interact with AGE will increase
  secretion of TNF-a, IL-6, and IL-1b

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Diabetes Mellitus - Hypothesis

• Interaction of AGE and endothelial cells will
  result in endothelin-1 (a potent vasoconstrictor)
• The previous cellular reactions may take place in
  the periodontium, thus accounting for increased
  risk for severe attachment loss
• Tissues from retina, kidney, and nerves have
  shown permeability to glucose
• Pathogenesis of periodontal disease in diabetics
  might also be glucose-mediated

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Diabetes

• IDDM and NIDDM are risk factors for periodontal
  disease
• Progression is faster and tooth loss is higher in
  poorly controlled patients
• PMN function might be impaired
• Thickening of the basement membrane and the
  vessel walls

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Diabetes

• Interference with delivery of nutrients
• Decreased oxygen diffusion
• Decreased elimination of metabolic waste
• Increased collagen breakdown
• Altered collagen synthesis

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Diabetes

• Well-controlled diabetics who receive regular
  periodontal care and have good oral hygiene are
  NO more likely to develop severe periodontitis
  than non diabetics.
• Seppala et al., 1993 and 1994
• Well-controlled diabetics have been shown to
  respond equally as well to periodontal therapy as
  non diabetics.
• Westfelt et al., 1996 Telervo et al., 1997

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Effect of Periodontitis on Diabetes

• Hypothesis
• Bacterial infection releases hormones that
  increase glucose levels
• Inflammatory mediators (TNF-a and IL-1b) induce
  cell resistance to insulin

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Effect of Periodontitis on Diabetes

• Periodontal treatment might improve the metabolic
  control of the disease
• Williams and Mahan, 1960 Miller et al., 1992
• Aldridge et al., 1996 Grossi et al., 1997
• Severe Periodontitis has been associated with a 6
  fold increased risk of poor glycemic control
  Taylor et al., 1996

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Cigarette Smoking

• Accounts for approximately half the cases of
  periodontitis in young adults
• Smokers are, in average, close to three times
  more likely to show severe periodontal disease
• Current smokers are 3.3 times more likely to
  attend a periodontists office

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Smoking

• Light smokers have a relative risk of developing
  periodontal disease that is 2 times higher than
  non smokers
• Heavy smokers have a relative risk of developing
  periodontal disease that is 7 times higher than
  non smokers
• Grossi et al. 1994, 1995

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Smoking

• Decreases cell-mediated and humoral immune
  responses
• Alters PMN function
• Decreases serum IgG2
• Modulates subgingival microbiota
• Increases levels of certain microorganisms

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Smoking Cessation

• Seems to yield periodontal benefits
• Long term studies are still missing
• After a year, gingival tissues revert from
  fibrotic to normal anatomy and contour
• Haber, 1996

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HIV

• Conflicting evidence to be considered a risk
  factor for conventional periodontal disease
• Small percentage of HIV patients develop a
  severe rapidly progressive form of
  gingivitis/periodontitis (NUG/NUP)
• Lesions are usually associated with pronounced
  immunosuppression

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HIV

• Regulation of PMN recruitment in GCF is hindered
• Suggested that PMN dysfunction allows subgingival
  colonization of Candida and subsequent risk
  increase for periodontal destruction
• Lamster et al., 1998

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Candidiasis and Periodontal Disease
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Short-Term Success of Osseointegrated Dental
Implants in HIV-Positive Individuals

• Riano PC, Stevenson GC, Engelmeier RL, Flaitz CM,
  Moretti AJ, Nichols CM

Master of Sciences Thesis at UTDB Houston
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Hypothesis

• The null hypothesis for this study was There
  are no differences between the HIV infected and
  uninfected populations in the clinical behavior
  and biologic integration of endosseous dental
  implants as measured by descriptive parameters of
  assessment.

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Study Information

• Prospective, cohort, multi-center pilot study
• Compare short-term success rate of
  osseointegrated dental implants in HIV infected
  versus uninfected populations to justify the use
  of implants in the HIV positive population
• Clinical study to glean other important clinical
  information related to implant dentistry in HIV
  infected individuals to assist dentists in
  contributing to the improvement of the quality of
  life for these individuals

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Materials and Methods

• 15 HIV patients
• 8 HIV- patients
• Inclusion criteria
• gt18 years old, edentulous for at least 2 years
• Occlusion type I or III
• Minimum of 10mm crestal height
• Hemoglobin gt8g/dl
• Absolute neutrophil count gt750 cells/L
• Platelet count gt75,000/L
• ASTlt5 times the upper limit of normal (ULN)
• Bilirrubin lt2.5 times ULN
• Alkaline phosphatase lt5.0 times ULN
• Creatinine lt2.5 mg/ml

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Materials and Methods

• Exclusion criteria
• Heavy smoking (gt30 cigarettes/day)
• Individuals with high recurrence of opportunistic
  infections
• Patients with uncontrolled diabetes mellitus
• Pregnant patients
• Occlusion class II and/or bruxism
• Inadequate bone availability
• Poor oral hygiene

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Materials and Methods

• Panoramic radiograph
• Surgical drill guide for mandible only
• Amoxicillin 500mg/chlorhexidine rinses
• Mandibular right and left block anesthesia
• Full thickness flaps
• Two BioHorizons implants Maestro System (s 22
  and 27) length 11 or 12 mm, diameter 3.5 to
  5.0mm
• Conventional surgical protocol according to
  Branemark

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Tooth Loss and Osteoporosis

• Systemic bone loss can be a risk for
  edentulism Daniell et al., 1983
• In a 7-year longitudinal study, the rate of
  systemic bone loss was a predictor for tooth loss
  in menopausal women Krall et al., 1996
• Women that are at risk for or suffer from
  osteoporosis are also at risk for tooth loss
• Grossi et al., 2000

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Periodontal Disease and Osteoporosis

• Mandibular bone mass is not related to age but to
  skeletal bone mass Kribbs et al., 1990
• Controversy still exists on the association
  between osteoporosis and periodontal disease
• Small sample size, age of population
• Definitions of diseases, methods used
• Grossi et al., 2000

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Menopause

• Postmenopausal women with no hormonal replacement
  have shown greater tooth loss
• Grodstein et al., 1996
• Women who received estrogen replacement had much
  lower risk for edentulism
• Pagaini-Hill, 1995

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Menopause

• Alendronate has shown to lower the risk of bone
  height and density loss by half
• This difference was shown to remain for at least
  three months after stopping treatment
• Jeffcoat and Reddy, 1996

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Angst-Related Psychosocial Factors

• Chronic stress
• Depression
• Financial problems
• Social Isolation

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Angst-Related Psychosocial Factors

• People with good coping strategies show less
  periodontal disease
• Moss et al., 1996 Marcenes and Sheiham, 1992
• Genco et al., 1999
• Studies needed establish the time course of
  stress, distress, and inadequate coping with
  respect to onset and progression of periodontal
  disease

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Periodontal disease as a risk factor for systemic
conditions

• Cardiovascular Disease
• Pregnancy
• Respiratory

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Cardiovascular Disease

• Increased risk for atherosclerosis and
  thromboembolisms due to periodontal disease
• Men with periodontitis is 25 more likely to
  develop coronary heart disease (CHD)
• The risk is particularly high for men under age
  50 with a relative risk for CHD
• DeStefano et al., 1993

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Mechanisms by which infections contribute to
atherosclerosis

• Direct effects of infectious agents in atheroma
  formation
• Indirect or host-mediated effects triggered by
  infection
• Common genetic predisposition to periodontal
  disease and atherosclerosis
• Common risk factors such as life style

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Direct effects of infectious agents in atheroma
formation

• P. gingivalis has been found in carotid and
  coronary atheromas
• Haraszthy et
  al. 1998 Chiu et al., 1999
• P. gingivalis has shown to invade and proliferate
  in endothelial cells
• 
  Deshpande et al., 1998
• P. gingivalis is able to induce aggregation of
  platelets
• Herzberg and Meyer, 1996

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Indirect or host-mediated effects triggered by
infection

• Periodontitis induces production of C-reactive
  protein and fibrinogen
• Periodontal microorganisms contain proteins which
  cross-react with the heart

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Common genetic predisposition to periodontal
disease and atherosclerosis

• Beck et al., 1996 proposed a model of genetically
  determined hyperinflammatory macrophage phenotype
  in periodontal disease, which contributes to the
  susceptibility for atherosclerosis

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Cardiovascular Disease

• Meta-analyses of prospective studies on coronary
  heart disease (CHD) and periodontal disease
  Danesh, 1999
• Five main studies with 2369 cases
• Weighted mean age at baseline of 55 years
• Weighted mean follow-up of 12 years

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Cardiovascular Disease

• Different methods to measure disease (including
  self reported)
• Different criteria based on clinical examination
  (e.g., missing teeth, alveolar bone loss,
  attachment loss, probing depth)
• There was no significant heterogeneity among the
  5 articles (p gt .1)

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Cardiovascular Disease

• This analyses did not find any strong correlation
  between periodontal disease and CHD
• Reliable investigation requires
• larger sample size
• socially homogeneous population
• serial measurements of infective agents
• studies of early-onset cases

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Pregnancy

• Fetuses of pregnant hamsters infected with P.
  gingivalis weighted up to 25 less than the
  fetuses of healthy controls
• 124 pregnant mothers with periodontal disease
  were seven times more likely to deliver a preterm
  low-birth weight (PLBW) baby
• Offenbacher et al., 1996

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Pregnancy

• F. nucleatum is the most frequent isolate from
  the amniotic fluid (AF)
• F. nucleatum may spread to the AF via a transient
  bacteremia in the presence of periodontal disease
• IL-1, IL-6, and TNF-a may target the placenta

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Pregnancy

• Mothers with a higher mean of GCF-PGE2 level were
  9 times more likely to be in PLBW
• There is also a trend of higher mean of GCF-IL-1b
  level and an increase in PLBW
• Offenbacher et al., 1998

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Respiratory

• Hospitalized or nursing home patients may
  increase the risk for bacterial pneumonia
• Scannapieco et al., 1998
• There is evidence of correlation between
  increased alveolar bone loss and increased risk
  for chronic obstructive pulmonary disease
• Hayes et al., 1998

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Evaluation of Oral Soft Tissue Lesions in
Ventilated Patients

• Moretti AJ, Flaitz CM, Peninger M, Rex JH, Milano
  M, Harrison N, and Nates JL

UTHSC-H Dental Branch and Medical
School, Memorial Hermann Hospital, Houston, TX
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Purpose

• To document the frequency of oral soft tissue
  lesions in ventilated patients, who were
  receiving care in a tertiary care and level I
  trauma center. This report is part of a larger
  study on oral hygiene care for these patients,
  using the oral suction toothbrush and oral swab.

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Materials and Methods

• Study features
• Pilot study, convenience sample, short term
• Neurosurgical Intensive Care Unit patients
• Treatment groups oral hygiene by two-sided
  sponge or sponge/toothbrush
• Oral hygiene q 4-6 h. or minimum 3 x/day
• Initial evaluation by oral pathologist and
  periodontist within 24 hours
• Follow up q 3-4 days
• High intensity light, mouth mirror, cheek
  retractors, photos of accessible lesions

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Materials and Methods

• Inclusion criteria
• Assisted ventilation gt48 h.
• Age gt18 years-old
• gt 2 teeth
• Exclusion criteria
• Non-ventilated patients
• Trauma to jaws or neck to limit oral access
• Transfer to another unit in less than 24 h.
• Life expectancy less than 24 h.
• Edentulous patients

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Materials and Methods

• Parameters
• Plaque Index (Silness and Löe, 1964)
• Gingival Index (Löe and Silness, 1963)
• Tongue assessment (amount, distribution and color
  of coating)
• Halitosis (Organoleptic scores, Rosenberg et al
  1991)
• Trauma associated oral lesions
• Other oral and perioral lesions

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Ventilated Patient
Swab Toothbrush
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Herpes Labialis
Purpura/Sloughing
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NUP/Candidiasis
Spontaneous bleeding
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Summary of Results

• At least one lesion per patient
• Observation time was similar for all patients
• More male patients in toothbrush group
• Similar PI and GI for both groups
• No difference in improvement of halitosis
• No difference in lesions in both groups

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Weaknesses of Study

• Very small sample size and limited time of
  observation
• Periodontal status not assessed prior to
  randomization
• More males in toothbrush group. Males usually
  have decreased periodontal health in comparison
  to females
• Limited accessibility to evaluate parameters

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Conclusions

• Lesions were very common but not associated with
  the oral hygiene devices
• Potential for oral lesions and periodontal
  disease to contribute to systemic complications
  exists because many of these lesions are
  ulcerative and infectious
• Medical and nursing staff needs to recognize and
  manage a variety of oral lesions for improved
  patient care and quality of life for ventilated
  patients

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Future knowledge in Periodontal Systemic
Interrelationships

• In vitro studies
• Animal studies
• Intervention studies

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Modulation of Host Inflammatory Mediators as a
Treatment Strategy for Periodontal Diseases

• Antonio J. Moretti, DDS, MS

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Historical Review

• Until 1970s bacteria and their products were seen
  as the most important factors in periodontal
  diseases.
• Page Schroeder (1976) pathogenesis of
  inflammatory periodontal disease.
• Inflammatory mediators (i.e., arachidonic acid
  metabolites and cytokines) directly cause local
  tissue destruction.
• Matrix metalloproteinases imbalance.

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Pharmaceutical Inhibition of Host Response
Pathways

• NSAIDs
• Cytokine receptor antagonists
• Anti-collagenolytic agents

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Modulation of Arachidonic Acid Metabolites

• Vane (1971) published landmark discovery that
  aspirin and NSAIDs blocked cyclooxygenase.
• El Attar (1976) PGE2 levels were observed 20
  times higher in the inflamed gingiva.
• Offenbacher et al. (1981) found elevated PGE2
  levels in the GCF of periodontitis patients.

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Modulation of Arachidonic Acid Metabolites

• Williams et al. (1985) NSAIDs in animal model.
• Williams et al. (1989) NSAIDs in humans showed
  significant lower bone loss rates up to 24
  months.
• Jeffcoat et al. (1995) NSAID rinse with positive
  results.

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Modulation of Arachidonic Acid Metabolites

• Standard NSAIDs inhibit both cyclooxygenase 1 and
  2.
• Side effects gastrointestinal tract, kidney, and
  platelets.
• New classes of agents (i.e., cyclooxygenase 2
  inhibitors and lipoxins) might selectively
  inhibit the isoenzyme associated with
  inflammation rather than that of tissue
  homeostasis.

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Modulation of Host Cytokines

• Cytokines literally cell proteins transmit
  information from one cell to another.
• IL-1b
• TNF-a
• Assuma et al. (1998) animal research on cytokine
  (i.e., IL-1b and TNF-a) receptor antagonists
  found 80 inhibition.

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Modulation of Other Host Inflammatory Mediators

• Nitric Oxide (NO)- free radical with important
  physiological functions including cardiovascular,
  nervous system and immune homeostasis.
• NO is elevated in inflammation to protect against
  antigens. It causes deleterious host effects such
  as DNA damage, peroxidation, protein damage, and
  release of cytokines.

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Modulation of Other Host Inflammatory Mediators

• Lohinai et al. (1998) - animal study with
  injection of mercaptoethylguanidine. Test group
  exhibited less plasma extravasation and less bone
  loss as compared with controls.

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Matrix Metalloproteinases (MMPs)

• MMPs are a family of at least 12 Ca and Zn
  dependent enzymes that degradate extracellular
  matrix macromolecules (i.e., interesticial and
  basement membrane collagens, fibronectins,
  laminin, and proteoglycan core proteins).

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MMPs

• Matrix metalloproteinases are produced by both
  infiltrating and resident cells of periodontium.
• They play a role in both physiological (i.e.,
  tooth eruption) and pathological (i.e.,
  periodontitis) events.

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Tetracyclines

• Non-antimicrobial properties have application in
  the treatment of
• Cancer
• Complications of diabetes
• Arthritis
• Wound healing

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MMPs (studies)

• Golub et al. 1980 tetracycline binding to Zn
  and Ca on collagenases.
• Animal studies (Ciancio et al. 1998)
• Human studies (Caton et al. 1997, 2000)

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Sub antimicrobial dose doxycycline(SDD)

• 20 mg bid (no antimicrobial action)
• No change in bacterial flora after 18 months
• No induction of resistance after 18 months
• Side effect profile similar to placebo

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Sub antimicrobial dose doxycycline(drawbacks)

• Compliance
• Cost
• Statistical x Clinical Significance

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Modulation of Host Inflammatory Mediators -
Conclusions

• Animal and human studies support the basic
  hypothesis that inhibition of local arachidonic
  acid metabolites with NSAIDs slows periodontal
  disease progression.
• Data on modulation of cytokines and Nitric Oxide
  appear promising.

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Modulation of Host Inflammatory Mediators -
Conclusions

• Despite the finding that SDD provides some
  benefit in arresting periodontal disease
  progression, there are numerous issues that need
  to be addressed before its widespread use with
  any form of periodontitis.

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Modulation of Host Inflammatory Mediators -
Conclusions

• Clinicians need to decide which patients are at
  greatest risk of future disease progression. We
  still lack proper diagnostic tools for this
  matter.
• These adjunctive forms of therapy may become a
  valid option for a small percentage of our
  patients.

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