Subantimicrobial Dose Doxycycline Treatment Research Articles

Sub-antimicrobial doses of doxycycline decreased bone loss related to ligature-induced periodontitis in hypertensive rats

Background/ObjectiveThe beneficial effects of sub-antimicrobial dose doxycycline (SDD) associated with nonsurgical periodontal therapy are well documented. Recently, the effects of SDD on metalloproteinases have been investigated in the treatment of hypertension. The aim of this study was to evaluate the effects of SDD on ligature-induced periodontitis in spontaneously hypertensive rats (SHR). MethodsFifty-four adult male rats were divided into three groups: SHR-C, SHR-L and SHR-L-DOX (C - Control; L – Ligature). In group SHR-L-DOX, animals were treated with daily 5 mg/kg SDD administration. In L groups, a ligature remained around mandibular first molars for the first 10 days. Each group was divided for euthanasia at 10 or 21 days. Microtomographic and histometric analyses were performed. Osteoclastogenesis was evaluated by tartrate-resistant acid phosphatase (TRAP) assay and gene expression of 84 inflammatory mediators by polymerase chain reaction (PCR) array. ResultsGroup SHR-L-DOX presented reduced systolic blood pressure when compared with group SHR-L at both 10 and 21 days (p < 0.05). Group SHR-L-DOX showed decreased bone and attachment loss in comparison with group SHR-L at both 10 and 21 days (p < 0.05). SDD treatment reduced the amount of TRAP-positive cells at 10 days (p < 0.05). Group SHR-L-DOX showed a downregulated inflammatory genes profile in comparison with SHR-L at 10 and 21 days. ConclusionSDD therapy exerted systemic modulatory effect on inflammation with reduced periodontal tissue destruction in hypertensive rats.

Downregulation of Proteinase-Activated Receptor-2, Interleukin-17, and Other Proinflammatory Genes by Subantimicrobial Doxycycline Dose in a Rat Periodontitis Model.

Subantimicrobial dose doxycycline (SDD) has been used as an adjunct in periodontal treatment because of its matrix metalloproteinase inhibition properties. Although the benefits of SDD therapy, such as improvement in the parameters of periodontal probing depth and clinical attachment level, have been proven in multiple clinical studies, the comprehension of other biologic mechanisms of action on periodontitis remains poorly investigated. Therefore, this animal-model study evaluated the effects of SDD monotherapy on the expressions of the following key proinflammatory genes: proteinase-activated receptor-2 (PAR2), tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-1β. Male Wistar rats were assigned randomly to the following: 1) control group: no ligature-induced periodontitis and no treatment; 2) ligature group: ligature-induced periodontitis and placebo treatment; and 3) ligature + doxycycline group: ligature-induced periodontitis and SDD treatment. After the experimental time, animals were sacrificed, and reverse transcription-polymerase chain reaction was performed to analyze the mRNA expression of IL-1β, IL-17, TNF-α, and PAR2 in gingival tissue samples. Histologic analyses were performed on the furcation region and mesial gingiva of mandibular first molars to measure periodontal bone loss and collagen content. SDD administration significantly downregulated PAR2, IL-17, TNF-α, and IL-1β mRNA expressions (P <0.05). In addition, SDD treatment was accompanied by lower rates of alveolar bone loss (P <0.05) and maintenance of the amount of gingival collagen fibers. These findings reveal new perspectives regarding SDD efficacy because it can be partially related to proinflammatory gene expression modulation, even considering PAR2 and IL-17, which has not been investigated thus far.

Subantimicrobial-dose doxycycline treatment increases serum cholesterol efflux capacity from macrophages

Subantimicrobial-dose doxycycline (SDD) treatment has been reported to reduce the severity of chronic inflammation and to increase serum high-density lipoprotein cholesterol. In a double-blind, placebo-controlled clinical trial, we determined whether SDD affects the ability of serum to facilitate cholesterol removal from macrophages. Forty-five postmenopausal osteopenic women with periodontitis were randomly assigned to take placebo (n = 26) or doxycycline hyclate (20 mg, n = 19) tablets twice daily for 2 years. Serum samples were collected at baseline, 1-, and 2-year appointments. The cholesterol efflux capacity of serum from cultured human macrophages (THP-1) was measured. SDD subjects demonstrated a significant increase in serum-mediated cholesterol efflux from macrophages at both time points compared to baseline (p < 0.04 for each). Mean cholesterol efflux levels over the first year of follow-up were 3.0 percentage points (unit change) higher among SDD subjects compared to placebo subjects (p = 0.010), while there was no significant difference in 2-year changes. There were no significant differences in the changes of apolipoprotein A-I, apolipoprotein A-II, or serum amyloid A levels between the groups. Our results suggest that SDD treatment may reduce the risk of cardiovascular disease in this patient group by increasing the cholesterol efflux capacity of serum.

The effect of sub-antimicrobial dose-doxycycline periodontal therapy on serum inflammatory biomarker C-reactive protein levels in post-menopausal Women: A 2-year, double-blinded, randomized clinical trial

Background:Periodontitis has been reported to be associated with coronary artery disease. Research is needed to determine whether therapies that improve periodontal health also reduce systemic marker of inflammation associated with both diseases.Aim:To determine whether sub-antimicrobial dose-doxycycline (SDD) therapy can reduce systemic serum inflammatory biomarker C-reactive protein (CRP) in post-menopausal women who have chronic periodontitis.Settings and Design:The study randomly assigned 128 eligible post-menopausal women with chronic periodontitis to a 90-day, twice-daily regimen of SDD or placebo tablets evaluated for 2 years, as an adjunct to periodontal maintenance therapy.Materials and Methods:The study assayed blood samples for inflammatory mediators at baseline, 1 year, and 2 years. CRP was measured using a high-sensitivity enzyme-linked immunosorbent assay.Results:SDD treatment reduced median high-sensitivity CRP by 18% (primary outcome = 0.02).Conclusion:Ninety-day SDD regimen in post-menopausal women significantly reduced the serum inflammatory biomarker CRP over a 2-year period.

The effect of subantimicrobial-dose–doxycycline periodontal therapy on serum biomarkers of systemic inflammation: A randomized, double-masked, placebo-controlled clinical trial

<h2>ABSTRACT</h2><h3>Background</h3> Periodontitis has been reported to be associated with coronary artery disease (CAD). Research is needed to determine if therapies that improve periodontal health also reduce systemic measures of inflammation associated with both diseases. <h3>Methods</h3> The study registrar randomly assigned 128 eligible postmenopausal women with chronic periodontitis to a twice-daily regimen of subantimicrobial-dose–doxycycline (SDD) or placebo tablets for two years as an adjunct to periodontal maintenance therapy. Through a supplement to the main trial, in which they investigated alveolar bone and clinical attachment level changes, the authors assayed inflammatory mediators and lipid profiles in baseline, one-year and two-year serum samples. The authors analyzed the data by using generalized estimating equations. <h3>Results</h3> In the intent-to-treat analysis across two years, SDD treatment reduced median high-sensitivity C-reactive protein (hs-CRP) by 18 percent (primary outcome; <i>P</i> = .02) and reduced serum matrix metalloproteinase (MMP)-9 (92 kilodalton gelatinase; difference in mean scanning units, −28.44; <i>P</i> < .001), with no significant effect on serum lipids. However, in women more than five years postmenopausal, SDD elevated the level of high-density lipoprotein (HDL) cholesterol (difference in means [milligrams per deciliter], 5.99; <i>P</i> = .01). <h3>Conclusion</h3> A two-year SDD regimen in postmenopausal women significantly reduced the serum inflammatory biomarkers hs-CRP and MMP-9 and, among women more than five years postmenopausal, increased the HDL cholesterol level. <h3>Clinical Implications</h3> SDD significantly reduced the systemic inflammatory biomarkers hs-CRP and MMP-9. More research is needed to determine whether SDD has a role in managing the care of patients at risk of developing CAD.

Subantimicrobial‐Dose Doxycycline Modulates Gingival Crevicular Fluid Biomarkers of Periodontitis in Postmenopausal Osteopenic Women

We recently demonstrated that a 2-year subantimicrobial-dose doxycycline (SDD) regimen (double-masked, placebo-controlled clinical trial) in postmenopausal (PM) women exhibiting mild systemic bone loss (osteopenia) and local bone loss (periodontitis) reduced the progression of periodontal attachment loss (intent-to-treat analysis) and the severity of gingival inflammation and alveolar bone loss (subgroups) without producing antibiotic side effects. We now describe SDD effects on biomarkers of collagen degradation and bone resorption in the gingival crevicular fluid (GCF) of the same vulnerable subjects. GCF was collected from SDD- and placebo-treated PM subjects (n=64 each) at the baseline and 1- and 2-year appointments; the volume was determined; and the samples were analyzed for collagenase activity (using a synthetic peptide as substrate), relative levels of three genetically distinct collagenases (Western blot), a type-1 collagen breakdown product/bone resorption marker (a carboxyterminal telopeptide cross-link fragment of type I collagen [ICTP]; radioimmunoassay), and interleukin-1beta (enzyme-linked immunosorbent assay). Statistical analyses were performed using generalized estimating equations; primary analyses were intent-to-treat. Collagenase activity was significantly reduced by SDD treatment relative to placebo based on intent-to-treat (P=0.01). ICTP showed a similar pattern of change during SDD treatment, and GCF collagenase activity and ICTP were positively correlated at all time periods (P<0.001). Matrix metalloproteinase (MMP)-8 accounted for approximately 80% of total collagenase in GCF, with much less MMP-1 and -13, and SDD reduced the odds of elevated MMP-8 by 60% compared to placebo (P=0.006). These observations support the therapeutic potential of long-term SDD therapy to reduce periodontal collagen breakdown and alveolar bone resorption in PM women; effects on serum biomarkers of systemic bone loss in these subjects are being analyzed.