{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:31:56Z","timestamp":1789810316178,"version":"4.0.1"},"reference-count":0,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2004,3,1]],"date-time":"2004-03-01T00:00:00Z","timestamp":1078099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Periodontology"],"published-print":{"date-parts":[[2004,3]]},"abstract":"Background:<\/jats:bold> 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\u2010resistant bacteria either orally or extra\u2010orally. 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\u2010steroidal anti\u2010inflammatory 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\u2010modulating drugs (SDD plus low\u2010dose 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\u2010derived proteinases including MMPs, indicated improved clinical efficacy of combination therapy.<\/jats:p>Methods:<\/jats:bold> Nineteen CP patients, scheduled for mucoperiosteal flap surgery bilaterally in the maxillary arch, were randomly distributed into three experimental groups administered either 1) low\u2010dose 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\u2010week regimen of medication, respectively. The tissues were then extracted, the extracts partially purified, then analyzed for the endogenous proteinase inhibitor, \u03b11\u2010PI, and its breakdown product, and for host\u2010derived matrix metalloproteinases (i.e., collagenases, gelatinases) and neutrophil elastase activities.<\/jats:p>Results:<\/jats:bold> Short\u2010term therapy with SDD alone produced a significant reduction and LDF alone produced no reduction in host\u2010derived neutral proteinases. However, the combination therapy produced a statistically significant synergistic reduction of collagenase, gelatinase, and serpinolytic (\u03b11\u2010PI degrading) activities (69%, 69%, and 75% reductions, respectively) and a lesser reduction of the serine proteinase, elastase (46%).<\/jats:p>Conclusions:<\/jats:bold> 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\u2010based MMP inhibitor in the inflammatory lesion, thus synergistically enhancing the efficacy of this medication. J Periodontol 2004;75:453\u2010463<\/jats:italic>.<\/jats:p>","DOI":"10.1902\/jop.2004.75.3.453","type":"journal-article","created":{"date-parts":[[2005,2,2]],"date-time":"2005-02-02T07:52:16Z","timestamp":1107330736000},"page":"453-463","source":"Crossref","is-referenced-by-count":121,"title":["Subantimicrobial Dose Doxycycline Efficacy as a Matrix Metalloproteinase Inhibitor in Chronic Periodontitis Patients Is Enhanced When Combined With a Non\u2010Steroidal Anti\u2010Inflammatory Drug"],"prefix":"10.1002","volume":"75","author":[{"given":"Hsi\u2010Ming","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian G.","family":"Ciancio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fclay","family":"T\u00fcter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Komaroff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorne M.","family":"Golub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,3]]},"container-title":["Journal of Periodontology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aap.onlinelibrary.wiley.com\/doi\/pdf\/10.1902\/jop.2004.75.3.453","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T11:35:20Z","timestamp":1760873720000},"score":1,"resource":{"primary":{"URL":"https:\/\/aap.onlinelibrary.wiley.com\/doi\/10.1902\/jop.2004.75.3.453"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,3]]},"references-count":0,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2004,3]]}},"alternative-id":["10.1902\/jop.2004.75.3.453"],"URL":"https:\/\/doi.org\/10.1902\/jop.2004.75.3.453","archive":["Portico"],"relation":{},"ISSN":["0022-3492","1943-3670"],"issn-type":[{"value":"0022-3492","type":"print"},{"value":"1943-3670","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,3]]}}}