Clinical studies on the management of periodontal diseases utilizing subantimicrobial dose doxycycline (SDD)

Department of Periodontology, Eastman Institute for Oral Health, University of Rochester, 625 Elmwood Avenue, Rochester, NY 14620, USA.
Pharmacological Research (Impact Factor: 4.41). 02/2011; 63(2):114-20. DOI: 10.1016/j.phrs.2010.12.003
Source: PubMed


Periodontitis, the most common chronic inflammatory condition known to mankind, is a disease that results in the destruction of tooth supporting tissues. Periodontitis is initiated by a bacterial biofilm on the tooth surface below the gingival margin. Until fairly recently it was assumed that the bacteria were the primary cause of tissue destruction, however, a large body of research has revealed that it is the patient's immune response that is actually responsible for the majority of the breakdown of tooth supporting tissues. Contemporary thinking suggests that successful, long term management of chronic periodontitis may combine both local mechanical and antimicrobial strategies to reduce the microbial bio-burden along with modulation of the host, patient's excessive, immuno-inflammatory response to the bacterial exposure known as host modulatory therapy (HMT). Based on extensive literature documenting the enzymatic inhibition and related anti-inflammatory properties of the tetracyclines, a new drug was developed as a host modulatory agent and approved by the United States Food and Drug Administration (FDA) for use as an adjunct to conventional scaling and root planing for the treatment of chronic periodontitis. A subantimicrobial dose of doxycycline (SDD) at 20 mg (Periostat(®)) has been found to be a safe and effective adjunct when taken twice daily for at least 3 months and up to 24 months in randomized placebo controlled clinical trials. Periostat(®) is currently the only FDA approved inhibitor of the matrix metalloproteinases implicated in the plaque-induced pathologic degradation of connective tissue collagen of the periodontal supporting structures. This review paper begins with a brief description of the disease process known as periodontitis followed by an extensive review of the Phase I-IV clinical trial data that established the safety and efficacy of sub-antimicrobial dose doxycycline (SDD) as an adjunct to scaling and root planing for the treatment of periodontitis.

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    • "Doxycycline can also be taken orally as a systemic adjunct to periodontal therapy. It is used at a low level that inhibits MMPs but does not have antimicrobial activity and thus does not select for antibiotic-resistant bacteria (Caton & Ryan, 2011). "
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    ABSTRACT: Locally applied therapeutic agents have become established in the treatment of periodontal disease. Inhibition of human metalloproteases by metal-chelating antibiotics contributes to the utility of local therapy. Adding inhibitors of bacterial proteases might extend and improve local therapy. The periodontal pathogen Porphyromonas gingivalis (Pg) produces two extracellular cysteine proteases (gingipains Rgp and Kgp) that are virulence factors and contribute to destruction of oral tissues. Our aims were to compare efficacy of protease inhibitors against gingipains and evaluate bactericidal activity of the inhibitors. Protease activity was measured in fluorescent assays with specific Rgp and Kgp substrates. Bacterial viability was measured with BacLight™ (Invitrogen, Inc., Carlsbad, CA) reagents. Pairs of inhibitors of Rgp and Kgp, respectively, were leupeptin and cathepsin B inhibitor II, KYT-1 and KYT-36, and PPACK and Z-FK-ck. The cysteine-protease inhibitor E64 was also tested. Rgp activity was higher than Kgp activity, and activity was higher in Pg 33277 and 49417 cell suspensions than in media. Concentrations required for 50% inhibition of Rgp in cell suspensions were 2 × 10−9, 2 × 10−9, 2 × 10−8, and 5 × 10−5 M for KYT-1, PPACK, leupeptin, and E64, respectively. Concentrations required for 50% Kgp inhibition were 5 × 10−10, 1 × 10−9, and 5 × 10−8 M for Z-FK-ck, KYT-36, and cathepsin B inhibitor II. E64 did not inhibit Kgp. Inhibition of Rgp could be accounted for by competition for binding between the arginine residue of the substrate and the guanidinobutane portion of E64. PPACK was the least selective, with a 10-fold difference in concentrations that inhibited Rgp and Kgp. KYT-1 and Z-FK-ck inhibited both Rgp and Kgp, but inhibitory concentrations differed by 10,000-fold. At up to 1 × 10−4 M, only Z-FK-ck was bactericidal. KYT-1 and KYT-36 were remarkably effective even when used in cell suspensions in which bacterial proteins could bind inhibitors or compete for binding to gingipains. These inhibitors might prove useful as an addition to locally applied therapeutic agents.
    Full-text · Article · Oct 2015
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    • "Aminov Biotic acts of antibiotics substantial inflammatory component (Del Rosso, 2007). Another FDA approval, after successful clinical trials, has been obtained for the long-term management of chronic periodontitis by subantimicrobial doses of doxycycline (SDD) (Caton and Ryan, 2011). This host modulatory therapy is directed against excessive MMPs activities that are implicated in degradation of connective tissue collagen surrounding and supporting the teeth. "
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    ABSTRACT: Biological functions of antibiotics are not limited to killing. The most likely function of antibiotics in natural microbial ecosystems is signaling. Does this signaling function of antibiotics also extend to the eukaryotic - in particular mammalian - cells? In this review, the host modulating properties of three classes of antibiotics (macrolides, tetracyclines, and β-lactams) will be briefly discussed. Antibiotics can be effective in treatment of a broad spectrum of diseases and pathological conditions other than those of infectious etiology and, in this capacity, may find widespread applications beyond the intended antimicrobial use. This use, however, should not compromise the primary function antibiotics are used for. The biological background for this inter-kingdom signaling is also discussed.
    Full-text · Article · Aug 2013 · Frontiers in Microbiology
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    • "Thus, it can be reasonably assumed that inhibitors/down-regulators of MMPs may have the potential to prevent and/or treat osteoarthritic symptoms and several other ECM-degradation diseases to some extent. Indeed, one MMP inhibitor, Periostat s , is currently available in clinics for treating periodontitis (Caton and Ryan, 2011). "
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    ABSTRACT: Among the mammalian matrix metalloproteinases (MMPs), MMP-1,–3 and -13 are collagenases. Particularly, MMP-13 is important for the degradation of major collagens in cartilage under certain pathological conditions such as osteoarthritis. To establish a potential therapeutic strategy for cartilage degradation disorders, the effects of 11 ginseng saponins (ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rg5, Rk1 and F4) on MMP-13 induction were examined in a human chondrocyte cell line, SW1353. Among these, several saponins including ginsenoside Rc, Rd, Rf, Rg3 and F4 were found to inhibit MMP-13 expression in IL-1β-treated SW1353 cells at non-cytotoxic concentrations (1–50 μM). The most prominent inhibitors were ginsenosides F4 and Rg3. Ginsenoside F4 inhibited MMP-13 expression 33.5% (P<0.05), 57.9% (P<0.01) and 90.0% (P<0.01) at 10, 30 and 50 μM, respectively. Significantly, ginsenoside F4 was found to strongly inhibit activation of p38 mitogen-activated protein kinase in signal transduction pathways (86.6 and 100.0% inhibition at 30 and 50 μM, P<0.01). The MMP-13 inhibitory effect was also supported by the finding that ginsenosides F4 and Rg3 reduced glycosaminoglycan release from IL-1α-treated rabbit joint cartilage culture to some degree. Taken together, these results indicate that several ginsenosides inhibit MMP-13 expression in IL-1β-treated chondrocytes. Ginsenoside F4 and Rg3 blocked cartilage breakdown in rabbit cartilage tissue culture. Thus, it is suggested that certain ginsenosides have therapeutic potential for preventing cartilage collagen matrix breakdown in diseased tissues such as those found in patients with arthritic disorders.
    Full-text · Article · Jan 2013 · European journal of pharmacology
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