Subantimicrobial Doses Of Doxycycline Research Articles

Host Response Modulation Therapy in the Diabetes Mellitus-Periodontitis Conjuncture: A Narrative Review.

The inflammatory response of the host in periodontitis is the phenomenon that underlies the onset and evolution of periodontal destructive phenomena. A number of systemic factors, such as diabetes mellitus (DM), can negatively affect the patient with periodontitis, just as the periodontal disease can aggravate the status of the DM patient. Host response modulation therapy involves the use of anti-inflammatory and anti-oxidant products aimed at resolving inflammation, stopping destructive processes, and promoting periodontal healing, all important aspects in patients with high tissue loss rates, such as diabetic patients. This paper reviews the data available in the literature on the relationship between DM and periodontitis, the main substances modulating the inflammatory response (nonsteroidal anti-inflammatory drugs, sub-antimicrobial doses of doxycycline, or omega-3 fatty acids and their products, specialized pro-resolving mediators), as well as their application in diabetic patients.

Role of adjunctive therapy with subantimicrobial doses of doxycycline in glycemic control (HbA1c) in patients with diabetes and endo-periodontal lesions to prevent sinus complications.

The present study aimed to analyze local and regional changes in regards to odontogenic sinusitis in subjects with endo-periodontal lesions and diabetes mellitus and to investigate the effect on the level of glycemic control (glycated hemoglobin) that could be generated by adjunctive therapy with subantimicrobial doses of doxycycline. This study was performed on 51 subjects with diabetes who were divided into two therapeutic groups: 31 patients with diabetes (the study group) who underwent conventional endo-periodontal therapy and subantimicrobial doses of doxycycline and 20 patients with diabetes who followed only conventional endo-periodontal therapy (the control group). Patients underwent endodontic and periodontal clinical examination, with retro-dental-alveolar radiographs and CBCT examinations. For each patient, glycated hemoglobin A1c (HbA1c) was determined. This evaluation was performed at the beginning of the study, as well as 3, 6 and 12 months after baseline. A significant percentage of patients, both in the study group and in the control group, showed radiological signs of odontogenic sinusitis, totaling 29 patients (56.86%). Periodontal parameters revealed lower levels in patients who underwent the regimen which consisted of subantimicrobial doses of doxycycline; these results were maintained over the study period. Moreover, we demonstrated significantly reduced glycated hemoglobin levels throughout the study (12 months) in the doxycycline-treated group. This fact has far-reaching effects in the sphere of loco-regional complications as well, and the risk of odontogenic sinusitis can be significantly reduced.

Doxycycline and Benznidazole Reduce the Profile of Th1, Th2, and Th17 Chemokines and Chemokine Receptors in Cardiac Tissue from Chronic Trypanosoma cruzi-Infected Dogs.

Chemokines (CKs) and chemokine receptors (CKR) promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox) in association, or not, with benznidazole (Bz) on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i) two months after infection, Dox (50 mg/kg) 2x/day for 12 months; (ii) nine months after infection, Bz (3,5 mg/kg) 2x/day for 60 days; (iii) Dox + Bz; and (iv) vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11), Th2 (CCL1, CCL17, CCL24, and CCL26), Th17 (CCL20) CKs, Th1 (CCR5, CCR6, and CXCR3), and Th2/Th17 (CCR3, CCR4, and CCR8) CKR, as well as IL-17. T. cruzi infection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection.

Clinical assessment of drug adjunctive therapy effects in association with chronic generalized periodontitis and osteoporotic disease

Aim: The present study proposes an assessment of the clinical effects on periodontal level generated by the adjunctive periodontal therapy with sub-antimicrobial doses of doxycycline in patients with chronic periodontitis and osteoporosis. Materials and Methods: The study group comprised 26 patients with chronic periodontitis and osteoporosis, divided in the study group (classical periodontal debridement and sub-antimicrobial doses of doxycycline for 3 months) and the control group (classical debridement only). We analyzed the periodontal parameters (probing depth, clinical attachment level, PBI and PI indices) at baseline, in the last day of medication and at 3 months after the drug therapy. Results and Discussion: The reduction of the moderate and profound pockets was higher for the group with drug adjunctive therapy. The sites with an initial depth of 0-3mm in the study group presented also a slight attachment gain. Conclusions: The therapy with sub-antimicrobial doses of doxycycline generated significant clinical improvement in patients with chronic periodontitis and osteoporosis, an improvement which can reduce the necessity of surgical procedures.

A histomorphometric study of the effect of doxycycline and erythromycin on bone formation in dental alveolar socket of rat.

Background:The aim of the present study was to evaluate whether subantimicrobial doses of doxycycline (DOX) and erythromycin (EM) used for the treatment of peri-implant osteolysis due to their anti-osteoclastogenesis can interfere with the osseous wound healing process in rat alveolar socket.Materials and Methods:Forty-five male Wistar rats had their first maxillary right molar extracted and were divided into three groups. DOX and EM at the doses of 5 mg/kg/day orally (p.o.) and 2 mg/kg/day intraperitoneally (i.p.) were administered respectively to two separate groups for 7 days after operation. In the control group the animals received normal saline (5 ml/kg). Five rats were sacrificed at 7, 14 and 21 days post-extraction in each study group. A histomorphometric analysis was used to evaluate new bone formation inside the alveolar socket. Significant level was set at 0.05.Results:The findings showed that the percentage of new bone formation (NBF) enhanced significantly on days 7 and 14. There was no significant difference in the NBF between DOX and EM groups.Conclusion:Short-term treatment with both DOX and EM enhanced new bone formation without any advances in favor of each drug.

The effect of doxycycline on shedding of the glycocalyx due to reactive oxygen species

The structure and composition of the endothelial cell (EC) glycocalyx reflect a balance of the biosynthesis of glycans and their shear dependent removal. Shedding of glycans from the EC surface has been shown to occur in response to reactive oxygen species (ROS) and inflammatory mediators. Using sub-antimicrobial doses of doxycycline, a broad spectrum matrix metalloprotease (MMP) inhibitor, inhibition of chemoattractant induced glycan shedding has suggested that MMPs may be a major effector of the loss of glycans. However, it has also been reported that doxycycline is a scavenger of ROS that may also activate MMPs. To clarify the basis for doxycycline as an inhibitor of glycan shedding, the present studies were undertaken to determine its effect on ROS induced shedding in post-capillary venules of the exteriorized mesentery of the rat. To this end, hypoxanthine (HX) and xanthine oxidase (XO) were rapidly mixed on the mesenteric surface for a 2min period to generate superoxide anion (O2−·) and the time course of glycan shedding was monitored in post-capillary venules over a 30min period. Glycan shedding was quantitated by loss of adherent fluorescently labeled lectin coated microspheres (FLMs, 0.1μm diameter) that were systemically infused. It was found that HX/XO caused FLM adhesion to decrease 45% within 30min. This effect could be inhibited in a dose dependent manner by the addition of superoxide dismutase to the superfusion solution, thus confirming the role of O2−·. In contrast, 0.5μM doxycycline had no effect on FLM shedding in response to HX/XO, contrary to its ability to attenuate shedding in response to the chemoattractant fMLP. Thus it is suggested that the efficacy of doxycycline as an inhibitor of glycan shedding during inflammation arises from its ability to inhibit MMP activation.

Doxycycline inhibits TREM-1 induction by Porphyromonas gingivalis

The triggering receptor expressed on myeloid cells 1 (TREM-1) is a cell surface receptor of the immunoglobulin superfamily, with the capacity to amplify pro-inflammatory cytokine production. Porphyromonas gingivalis is a Gram-negative anaerobic species highly implicated in inflammatory periodontal disease, with potential involvement in systemic inflammation. Porphyromonas gingivalis positively regulates TREM-1 expression and production in monocytic cells. Subantimicrobial doses of doxycycline (SDD) are used as an adjunct treatment in periodontal therapy, because of their anti-inflammatory properties. The aim of this study was to investigate the effect of SDD on P. gingivalis-induced TREM-1 expression and secretion by the myelomonocytic cell line MonoMac-6. After 24 h of challenge, P. gingivalis enhanced TREM-1 gene expression by the cells, with a concomitant increase in soluble TREM-1 release. Nevertheless, SDD concentrations between 2 and 10 μg mL(-1) abolished TREM-1 expression and release, already after 4 h of administration. Moreover, SDD reduced P. gingivalis-induced interleukin-8 secretion, confirming its anti-inflammatory effects. In conclusion, SDD inhibits bacterially induced TREM-1, and this effect may partly account for its generalized anti-inflammatory properties. This could partly explain the clinical efficacy of SDD as an adjunctive treatment for periodontal disease, but may also indicate that SDD could serve as a suitable modulator of systemic inflammatory responses.

The Endothelial Glycocalyx as a Barrier to Leukocyte Adhesion and Its Mediation by Extracellular Proteases

The endothelial cell (EC) surface is coated with a layer of polysaccharides linked to membrane-bound and trans-membrane proteoglycans that comprise the glycocalyx, which is augmented by adsorbed proteins derived from the blood stream. This surface layer has been shown to affect hemodynamics in small blood vessels of the microcirculation, the resistance to flow, and leukocyte (WBC) to EC adhesion. Parallel studies of WBC-EC adhesion in response to chemoattractants and cytokines, and shedding of constituents of the glycocalyx, have suggested a role for activation of extracellular proteases in mediating the dynamics of WBC adhesion in response to inflammatory and ischemic stimuli. Likely candidates among the many proteases present are the matrix metalloproteases (MMPs). Inhibition of MMP activation with sub-antimicrobial doses of doxycycline, or zinc chelators, has also inhibited WBC adhesion and shedding of glycans from the EC surface in response to the chemoattractant fMLP. Taken together, these studies suggest that shedding of the EC glycocalyx exposes adhesion receptors and thus enhances WBC-EC adhesion. Future therapeutic strategies for treating pathologies such as the low flow state and inflammation may benefit by further exploration of the mechanics of the glycocalyx in light of protease activation and shear-dependent effects.

Matrix metalloproteinase inhibition with tetracyclines for the treatment of coronary artery disease

Coronary artery disease is caused by atherosclerosis – a progressive arterial inflammatory disease that is responsible for significant global mortality and morbidity through the development of the acute coronary syndromes: sudden cardiac death, acute myocardial infarction and unstable angina. These clinical entities share a common pathophysiology: rupture of atherosclerotic plaque resulting in abrupt complete or partial thrombotic obstruction of coronary blood flow. Matrix metalloproteinases (MMP), through their central role in tissue remodeling and inflammation, are secreted by inflammatory cells of the atherosclerotic plaque and are capable of degrading all the extracellular matrix components of the fibrous cap that separates the atherosclerotic lesion from blood flow in the arterial lumen. Plaque rupture occurs when the circumferential tensile stresses in the artery overwhelm the structural integrity of the progressively degraded, thinned and weakened fibrous cap of the atherosclerotic lesion. Tetracyclines inhibit MMPs through their ability to chelate zinc. Subantimicrobial doses of doxycycline have been shown to reduce inflammation and inhibit MMP activity in patients with coronary artery disease. Further investigation is warranted to assess the potential clinical risks and benefits of MMP inhibition with tetracyclines or other agents in the treatment of coronary artery disease.

Pilot study: digital subtraction radiography as a tool to assess alveolar bone changes in periodontitis patients under treatment with subantimicrobial doses of doxycycline

Subtle changes in marginal alveolar bone level can be demonstrated using digital subtraction of sequential radiographs. We aimed to evaluate the practical application of geometrically corrected digital subtraction in a clinical study of alveolar bone response to a drug previously shown to inhibit alveolar bone loss. Selected periapical radiographs were acquired with projective standardization of patients with clinical marginal alveolar bone loss. Subsequently, patients received a 6-month regimen of subantimicrobial doxycycline or placebo. Standardized radiographs of the same alveolar regions were acquired after 3 and 6 months, and baseline radiographs were subtracted from these images. Blinded digital subtraction analysis indicated various levels of marginal bone gain in 3 of the 6 patients in the experimental group, whereas in 3 of the 5 placebo patients the method showed bone loss. These results suggest that geometrically corrected digital subtraction possibly agrees with clinical predictors of bone loss severity.

Low-dose doxycycline prevents inflammatory bone resorption in rats.

Matrix metalloproteinases (MMP) are considered to be key initiators of collagen degradation, thus contributing to bone resorption in inflammatory diseases. We determined whether subantimicrobial doses of doxycycline (DX) (< or =10 mg kg-1 day-1), a known MMP inhibitor, could inhibit bone resorption in an experimental periodontitis model. Thirty male Wistar rats (180-200 g) were subjected to placement of a nylon thread ligature around the maxillary molars and sacrificed after 7 days. Alveolar bone loss (ABL) was measured macroscopically in one hemiarcade and the contralateral hemiarcade was processed for histopathologic analysis. Groups of six animals each were treated with DX (2.5, 5 or 10 mg kg-1 day-1, sc, 7 days) and compared to nontreated (NT) rats. NT rats displayed significant ABL, severe mononuclear cell influx and increase in osteoclast numbers, which were significantly reduced by 5 or 10 mg kg-1 day-1 DX. These data show that DX inhibits inflammatory bone resorption in a manner that is independent of its antimicrobial properties.

Adjunctive treatment with subantimicrobial doses of doxycycline: effects on gingival fluid collagenase activity and attachment loss in adult periodontitis

The therapeutic effects of doxycycline and other tetracyclines in the treatment of periodontitis involve, at least in part, mechanisms that are unrelated to their antimicrobial activity. Previous clinical studies have shown that doxycycline administered orally, at doses below those needed for antimicrobial efficacy, to human subjects with adult periodontitis resulted in significantly reduced collagenase activity in gingival crevicular fluid (GCF) and in extracts of inflamed gingival tissues. The purpose of the present study was to identify clinically effective dosing regimens using subantimicrobial dose doxycycline (SDD) as an adjunctive therapy in patients with adult periodontitis. A total of 75 adult men and women qualified for enrollment into the three-part, placebo-controlled, double-blind, parallel-group study. Patients were stratified based on repeatedly exhibiting pathologic levels of periodontal attachment (ALv) and GCF collagenase activity at several appointments prior to baseline. Patients were administered a scaling and prophylaxis, then 1 of 5 treatment schedules for 12 weeks (part I), followed by a 12-week period of no drug therapy (part II), a second scaling and prophylaxis, and 12 additional weeks of treatment (part III). Primary determinants of efficacy included reductions in GCF collagenase activity and changes in relative ALv. 66 patients completed the 1st 12 weeks (part I) of the 3-part, 36-week study; 51 patients completed the entire 36-week study. From baseline to week 12 (part I), treatment with specially formulated SDD capsules (20 mg) 2x daily (1 x every 12 h) for up to 12 weeks was shown to significantly reduce GCF collagenase activity and to improve ALv, effects not seen in patients treated with placebo. Continuous drug therapy over the 12-week treatment period was needed to maintain and maximize the reduction in GCF collagenase and the improvement in ALv. Improvements in periodontal disease parameters occurred without the emergence of doxycycline-resistant micro-organisms. In patients administered an "on-off-on" regimen of SDD over 36 weeks (parts I-III), essentially no attachment loss occurred in patients receiving the highest of these SDD regimens (20 mg 2x daily during part I and 20 mg 1 x daily in part III), whereas patients administered placebo capsules experienced a mean attachment loss of approximately 0.8 mm at the 24- and 36-week time periods. Doxycycline administered at subantimicrobial doses led to improvements in disease parameters, with no apparent side effects, and appears to have significant potential as an oral adjunctive therapy in the long-term management of adult periodontitis.