title: Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug.
abstract: BACKGROUND
  Administration of subantimicrobial dose doxycycline (SDD) to chronic periodontitis (CP) patients has repeatedly been found to reduce mammalian collagenase and other matrix metalloproteinase (MMP) activity in gingival tissues and crevicular fluid, in association with clinical efficacy, without the emergence of antibiotic-resistant bacteria either orally or extra-orally. More recently, SDD adjunctive to repeated mechanical debridement resulted in dramatic clinical improvement in patients (>50% smokers) with generalized aggressive periodontitis. As an additional pharmacologic approach, non-steroidal anti-inflammatory drugs (NSAIDs) can reduce gingival inflammation and alveolar bone resorption, at least under experimental conditions. In the current study, we determined the effect of administering a combination (combination) of these two host-modulating drugs (SDD plus low-dose NSAID) to CP patients, on selected neutral proteinases in gingiva, enzymes believed to mediate periodontal breakdown. Earlier preliminary studies in humans with bullous pemphigoid, which is also associated with excessive levels of host-derived proteinases including MMPs, indicated improved clinical efficacy of combination therapy.
  
  
  METHODS
  Nineteen CP patients, scheduled for mucoperiosteal flap surgery bilaterally in the maxillary arch, were randomly distributed into three experimental groups administered either 1) low-dose flurbiprofen (LDF) alone, 50 mg q.d.; 2) SDD (20 mg b.i.d.) alone; or 3) a combination of SDD plus LDF (combination). The gingival tissues were biopsied during surgery from right and left maxillary posterior sextants, before and after a 3-week regimen of medication, respectively. The tissues were then extracted, the extracts partially purified, then analyzed for the endogenous proteinase inhibitor, alpha1-PI, and its breakdown product, and for host-derived matrix metalloproteinases (i.e., collagenases, gelatinases) and neutrophil elastase activities.
  
  
  RESULTS
  Short-term therapy with SDD alone produced a significant reduction and LDF alone produced no reduction in host-derived neutral proteinases. However, the combination therapy produced a statistically significant synergistic reduction of collagenase, gelatinase, and serpinolytic (alpha1-PI degrading) activities (69%, 69%, and 75% reductions, respectively) and a lesser reduction of the serine proteinase, elastase (46%).
  
  
  CONCLUSIONS
  Consistent with previous studies on animal models of chronic destructive disease (e.g., rheumatoid arthritis), the SDD and NSAID combination therapy synergistically suppressed MMP and other neutral proteinases in the gingiva of CP patients. A mechanism, suggested by earlier animal studies, involves the NSAID, in the combination regimen, increasing the uptake of the tetracycline-based MMP inhibitor in the inflammatory lesion, thus synergistically enhancing the efficacy of this medication.
authors.affiliation: Department of Oral Biology and Pathology, School of Dental Medicine, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
authors.forename: Hsi-Ming
authors.initials: HM
authors.lastname: Lee
authors.forename: Sebastian G
authors.initials: SG
authors.lastname: Ciancio
authors.forename: Gülay
authors.initials: G
authors.lastname: Tüter
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ryan
authors.forename: Eugene
authors.initials: E
authors.lastname: Komaroff
authors.forename: Lorne M
authors.initials: LM
authors.lastname: Golub
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002908:Chronic Disease; D017364:Collagenases / Q000032:analysis; D004318:Doxycycline / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005480:Flurbiprofen / Q000008:administration & dosage / Q000627:therapeutic use; D005500:Follow-Up Studies; D018093:Gelatinases / Q000032:analysis / Q000037:antagonists & inhibitors; D006801:Humans; D019272:Leukocyte Elastase / Q000032:analysis / Q000037:antagonists & inhibitors; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D010518:Periodontitis / Q000188:drug therapy*; D015842:Serine Proteinase Inhibitors / Q000032:analysis; D013524:Surgical Flaps; D000515:alpha 1-Antitrypsin / Q000032:analysis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D005480:Flurbiprofen; D019272:Leukocyte Elastase; D017364:Collagenases; D018093:Gelatinases; D004318:Doxycycline