BACKGROUND:Stannous fluoride has long been an effective antibacterial, anticaries, antisensitivity, and antigingivitis addition to toothpaste formulas. However, in the past its chemical properties in aqueous solution have made it difficult to stabilize with desirable results. The recent development of a novel formulation of 0.454% stannous fluoride stabilized with nitrate and phosphates (SNaP) has resulted in prolonged therapeutic effect without compromising product experience and esthetics. METHODS:Dentifrice antibacterial performance in vitro was determined through bacterial bioenergetics measured via rate of oxygen consumption and extracellular acidification in real-time comparing the SNaP toothpaste, a stannous fluoride positive control toothpaste, a non-antibacterial negative control toothpaste, and no treatment. Also, a single- center, randomized, controlled, double-blinded, clinical investigation of 98 subjects was performed to analyze dentifrice antibacterial performance in vivo following twice daily treatment with SNaP toothpaste (n = 48) and non-antibacterial control toothpaste (n = 50). Oral microenvironments, including plaque, tongue, cheek, gum, and saliva, of study participants 12 hours post-brushing were analyzed for bacterial load at baseline, 2 weeks, and 4 weeks. RESULTS:In vitro treatment of biofilms with SNaP toothpaste resulted in significant suppression of bacterial respiration and glycolysis compared to a positive control, negative control, and no treatment. In the clinical trial, treatment with SNaP toothpaste showed significantly lower bacterial load in all oral microenvironments 12 hours post-brushing after 2 weeks (all: P less than .01) and 4 weeks (all: P less than .05) compared to non-antibacterial negative control toothpaste. Compared to baseline, SNaP toothpaste significantly reduced bacteria from tongue (P = .007) and saliva (P less than .001) at week 2, and from all microenvironments by week 4 (all: P ≤ .001). CONCLUSIONS:SNaP toothpaste provided significantly greater and more sustained antibacterial effects than other tested toothpastes. Stannous fluoride, when stabilized in the SNaP formulation, effectively inhibited bacterial respiration and glycolysis in saliva-derived in vitro biofilms. The specific stabilization strategy used in SNaP toothpaste is critical for the antibacterial performance of stannous fluoride, as this formulation was more effective at reducing bacterial metabolic activity than a toothpaste containing the same amount of stannous fluoride stabilized with gluconate. The clinical study supports the in vitro findings by showing that the regular use of SNaP toothpaste leads to a significant and prolonged reduction in viable bacterial counts of five oral microenvironments. PRACTICAL IMPLICATIONS:The highly stabilized stannous ion in SNaP toothpaste confers potent, sustained antibacterial activity that can contribute to improved oral hygiene and potentially reduce the risk of tooth decay, early gum disease, calculus, and halitosis, which have been linked to oral bacteria.

BACKGROUND:Oral malodor, whether from systemic disease, dietary sources, or bacteria in the oral cavity, can negatively impact patients' quality of life. Oral malodor due to bacteria in the oral cavity can be managed by mechanically or chemically removing bacteria. Dentifrices are ideal vehicles to deliver therapeutic active ingredients that promote and maintain oral health since most consumers brush their teeth daily. Consumer preference drives consistency in oral hygiene routine. This study first identified a favorite flavor via consumer flavor testing and then measured the clinical efficacy of the dentifrice with a new flavor formulation to reduce malodor. METHODS:Consumer testing was conducted via an online product evaluation questionnaire to gauge consumer flavor preferences for stannous fluoride toothpaste stabilized with nitrate and phosphates (SNaP). In a 3-week randomized, single-center, double-blind clinical study, the malodor reduction ability of SNaP was compared to the negative control toothpaste containing 0.76% sodium monofluorophosphate via the organoleptic method. RESULTS:Consumer testing was used to determine a winning flavor for the new flavor formulation of SNaP tested in the clinical study. In this study, after 3 weeks of product use, on average, malodor clinical trial subjects (n = 97) randomized into the SNaP group had a 32.7% malodor score reduction from baseline (P less than .001) 12 hours post-brushing compared to a 9.4% reduction in the negative control group. Relative to the negative control group, the SNaP group had a statistically significant reduction of 25.7% (P less than .001) in oral malodor via organoleptic scores. CONCLUSIONS:SNaP toothpaste delivered superior malodor reduction 12 hours post-brushing when compared to a negative control toothpaste. PRACTICAL IMPLICATIONS:Incorporating therapeutic active ingredients like stannous fluoride into toothpaste is an effective way to deliver oral health benefits, such as caries prevention, reduction in gingivitis and dentin hypersensitivity, and protection against enamel erosion and bad breath.

OBJECTIVE/AIM:Optimal oral health behaviours are crucial to avoid preventable dental diseases and maintain good oral health. This research aimed to evaluate the impact of a digital oral health intervention (Know Your OQ™) in changing knowledge, attitudes and practices related to oral health.MATERIALS & METHODS:Two studies were conducted with a total of 296 healthy adults. Demographic data as well as knowledge, attitudes, and practices (KAPs) related to oral health were collected before and after completion of the Know Your OQ™ intervention. The KAPs questionnaire included 19 multiple choice questions. Comprehension and feedback were also collected.RESULTS:In total, 134 (45%) male and 162 (55%) female participants completed the two studies. Across both studies, 5 out of 7 knowledge questions and 2 out of 5 attitude questions showed significant changes pre/post-intervention with participants increasing their knowledge and improving their attitudes towards oral health. Only 1 practice changed in the first study, however, in the second study, 4 out of 7 practice questions showed significant changes pre/post-intervention. Comprehensibility was high across both studies with overall, positive feedback on the intervention.CONCLUSION:A digital oral health intervention was successful in increasing knowledge, changing attitudes and self-reported practices with regards to oral health in a diverse sample of the US population.

Objective To determine the effect of a semi-synthetic-glycosaminoglycan Ether (SAGE) as a universal therapeutic benefit to reduce periodontal inflammation and alveolar bone loss in naturally occurring-beagle-dog model of periodontal disease as a surrogate for human non-risk associated natural periodontitis. Methods Six adult female dogs with generalized periodontitis were distributed into two groups: control and SAGE treatment (n=3/group). After a 1-hour full-mouth scaling and root planning (SRP) at baseline, control or SAGE treatment (50mg/mL) bioadhesive gel formulation was locally applied for 12 weeks. Various clinical periodontal measurements (probing depth, CAL) were measured at different time periods (baseline, 4, 8 and 12 weeks), and gingival crevicular fluid (GCF), blood samples and gingival tissue biopsies (12 week) were analyzed for inflammatory mediators, collagenases and cell-signaling molecules. Standardized radiographs were taken at baseline and 12week period. Results SAGE treatment significantly reduced gingival inflammation (GCF flow), pocket depth (PD), and clinical attachment loss (CAL) compared to control. SAGE also considerably reduced alveolar bone loss and reduced MMP-9, IL-6, CRP levels in gingival tissue, GCF and plasma. Cell-signaling molecules in the inflammatory cascade system TLR-2, TLR-4, p38 MAPK, ERK1/2 and NF-kB responded to SAGE in a pattern consistent with reductions at the active phase of the inflammatory process and collagenolysis. Conclusion In the beagle dog model of periodontitis, local SAGE administration significantly attenuated clinical measures of periodontitis, pro-inflammatory cytokines, MMPs, and signal transduction molecules. All our studies, using in vitro and in vivo models, support the therapeutic potential of SAGE as an innovative adjunct to SRP in the treatment of chronic periodontal disease.

Background. The authors of this study aimed to evaluate the clinical antiplaque and antigingivitis effects of 3 oral hygiene regimens: toothbrushing with standard fluoride toothpaste and manual toothbrush and using a mouthrinse containing cetylpyridinium chloride, zinc lactate, and fluoride (CPC + Zn + F) in an alcohol-free base; toothbrushing with standard fluoride toothpaste and manual toothbrush and using a mouthrinse containing essential oils (EO) in an alcohol-free base; and toothbrushing with manual toothbrush and standard fluoride toothpaste and manual toothbrush (control). Methods. The participants (N = 120) were randomly assigned to study groups and followed the assigned regimens twice daily for 6 weeks. The participants were examined by a calibrated examiner for the Quigley-Hein plaque index (Turesky modification) and Loe-Silness gingival index at baseline, week 4, and week 6. Statistical analyses were performed separately for plaque and gingival indexes by means of analysis of variance, paired t test, and analysis of covariance (alpha = 0.05). Results. At week 4, the CPC + Zn + F group presented additional reductions in dental plaque compared with EO and control groups of (21.4% [ P < .001] and 31.4% [ P < .001], respectively). After 6 weeks, these values were 26.7% ( P < .001) and 44.8% ( P < .001), respectively. For Loe-Silness gingival index, additional reduction in the CPC + Zn + F group compared with EO were 10.6% ( P < .001) and 13.7% ( P < .001) at 4 and 6 weeks, respectively. Compared with control, these reductions were 13.6% ( P < .001) and 17.8% ( P < .001), respectively. Conclusions. The regimen including a mouthrinse containing CPC + Zn + F presented higher antiplaque and antigingivitis effects than EO and control regimens. Practical Implications. A mouthrinse containing CPC + Zn + F is an effective protocol for the control of dental plaque and gingivitis.

Dental caries can be effectively managed and prevented from developing into cavitated lesions while preserving tooth structure at all levels. However, the strong correlation between caries and socioeconomic factors may compromise the efficacy of preventive strategies. The high prevalence of persistent inequalities in dental caries in Latin American and Caribbean countries (LACC) is a matter of concern. The estimates of the burden of disease in some countries in this region are outdated or absent. This paper aims to summarize and present the final recommendations of a regional Consensus for Dental Caries Prevalence, Prospects, and Challenges for LACC. This consensus is based on four articles that were written by a team of Latin American experts, reviewed by dental associations, and presented and discussed in two consensus events. The following domains were explored: epidemiology, risk factors, prevention strategies, and management of dental caries with a focus on restorative procedures. Dental caries can manifest throughout the lifespan of an individual, making it a matter of concern for infants, children, adults, and older people alike. The prevalence rates of untreated caries in deciduous and permanent teeth are high in many parts of the world, including LACCs. Previous evidence suggests that the prevalence of dental caries in 12-year-olds is moderate to high in most Latin American countries. Moreover, the prevalence of treatment needs and dental caries in the adult and elderly population can also be regarded as high in this region. The risk/protective factors (e.g., sugar consumption, exposure to fluoride, and oral hygiene) probably operate similarly in all LACCs, although variations in the interplay of these factors in some countries and within the same country cannot be ruled out. Although salt and water fluoridation programs are implemented in many countries, there is a need for implementation of a surveillance policy. There is also room for improvement with regard to the introduction of minimal intervention techniques in practice and public health programs. Dental caries is a marker of social disadvantage, and oral health promotion programs and interventions aimed at reducing the burden of dental caries in LACCs must consider the complexity of the socioeconomic dynamics in this region. There is an urgent need to promote engagement of stakeholders, policymakers, medical personnel, universities, dental associations, community members, and industries to develop regional plans that enhance the oral health agenda for LACCs. A list of recommendations has been presented to underpin strategies aimed at reducing the prevalence and severity of dental caries and improving the quality of life of the impacted LACC population in the near future.

PURPOSE:This pilot study assessed the periodontal status and biomarkers of systemic inflammation in acute coronary syndrome (ACS) patients.METHODS:15 ACS patients on statin (anti-cholesterol) therapy, were recruited into the study an average of 9 months after discharge from university hospital. Blood and mouthrinse samples were collected for analysis of inflammatory biomarkers including high sensitivity C-reactive protein (hsCRP), IL-6, IL-1β, TNF-α, and MMP-9. Full-mouth periodontal examination, including pocket depth (PD), clinical attachment levels (CAL), bleeding on probing (BOP), and tooth mobility, was performed.RESULTS:When their periodontal status was assessed by CAL, 100% of these statin-treated ACS patients exhibited moderate (66.7%) to severe (33.3%) periodontal disease, which appears to be higher than the rate described for the general adult population (i.e., 47% for periodontitis). In addition, (1) their blood hsCRP levels ranged from 0.94 to 12.6 mg/L with a mean of 3.41 mg/L, which is considered high risk for cardiovascular disease (CVD) in spite of their statin therapy, and (2) the data demonstrated a positive correlation between severe periodontitis and elevated blood hsCRP levels (P< 0.05), consistent with systemic inflammation.CLINICAL SIGNIFICANCE:This pilot study provides preliminary data for future large-scale studies to define the relationship between ACS and chronic periodontitis, the underlying mechanisms, and the potential therapeutic efficacy of appropriate periodontal management to reduce the risk for cardiovascular disease.

The saliva of patients with COVID-19 has a high SARS-CoV-2 viral load. The risk of spreading the virus is high, and procedures for viral load reduction in the oral cavity are important. Little research to date has been performed on the effect of mouthwashes on the salivary SARS-CoV-2 viral load. This pilot randomized single-center clinical trial investigated whether three types of mouthwash with solutions containing either 0.075% cetylpyridinium chloride plus 0.28% zinc lactate (CPC + Zn), 1.5% hydrogen peroxide (HP), or 0.12% chlorhexidine gluconate (CHX) reduce the SARS-CoV-2 viral load in saliva at different time points. Sixty SARS-CoV-2-positive patients were recruited and randomly partitioned into a placebo (oral rinsing with distilled water) group and other groups according to the type of mouthwash. Saliva samples were collected from the participants before rinsing (T0), immediately after rinsing (T1), 30 min after rinsing (T2), and 60 min after rinsing (T3). The salivary SARS-CoV-2 viral load was measured by qRT-PCR assays. Rinsing with HP and CPC + Zn resulted in better reductions in viral load, with 15.8 ± 0.08- and 20.4 ± 3.7-fold reductions at T1, respectively. Although the CPC + Zn group maintained a 2.6 ± 0.1-fold reduction at T3, this trend was not observed for HP. HP mouthwash resulted in a significant reduction in the SARS-CoV-2 viral load up to 30 min after rinsing (6.5 ± 3.4). The CHX mouthwash significantly reduced the viral load at T1, T2, and T3 (2.1 ± 1.5-, 6.2 ± 3.8-, and 4.2 ± 2.4-fold reductions, respectively). In conclusion, mouthwash with CPC + Zinc and CHX resulted in significant reductions of the SARS-CoV-2 viral load in saliva up to 60 mins after rinsing, while HP mouthwash resulted in a significant reduction up to 30 mins after rinsing. Despite this transitory effect, these results encourage further studies and suggest that these products could be considered as risk-mitigation strategies for patients infected with SARS-CoV-2.

Background Chronic periodontitis is associated with an increased risk for systemic conditions such as cardiovascular disease, diabetes, and osteoporosis. During chronic periodontitis, endotoxin (lipopolysaccharide, LPS) produced by P. gingivalis provokes monocyte accumulation and differentiation into macrophages and increased secretion of pro-inflammatory cytokines and matrix metalloproteases (MMPs). While normal levels of MMPs are important in cellular function, increased levels of cytokines and MMPs can cause connective tissue destruction. Results In the current study, we investigated the therapeutic capability of a novel semi-synthetic sulfated polysaccharide (SAGE) on the production of cytokines and MMPs by cultured human mononuclear cells and macrophages stimulated with endotoxin LPS produced by P. gingivalis , a periodontally-relevant cell culture model. Our research demonstrated SAGE inhibited the LPS induced synthesis of inflammatory mediators including TNF-α, IL-1β, PGE 2 , and MMP-9 in this periodontal-relevant cell culture model. In addition, TLR-2 and TLR-4 levels were also reduced with the SAGE treatment. Conclusions The therapeutic potential of this novel semi-synthetic sulfated polysaccharide compound may help to prevent tissue damage and bone loss in patients with periodontal disease or other inflammatory diseases.

Periodontal diseases are considered a worldwide public health problem, owing to their high prevalence in developed and developing countries. Periodontitis may lead to tooth loss, which can impact oral health-related quality of life. Gingivitis and periodontitis have been extensively studied regarding their etiopathogenesis, epidemiology, prevention and treatment outcomes. However, most of these aspects are studied and discussed globally, which may hamper a clear interpretation of the findings and the design of effective plans of action for specific regions or populations. For example, in Latin America, epidemiological data about the distribution of periodontal diseases is still scarce, mainly when it comes to nationwide representative samples. This Consensus aimed to address the following topics related to periodontal diseases in Latin America: a) The impact of the global burden of periodontal diseases on health: a global reality; b) Periodontal diseases in Latin America; c) Strategies for the prevention of periodontal diseases in Latin America; d) Problems associated with diagnosis of periodontal conditions and possible solutions for Latin America; e) Treatment of Periodontitis. This consensus will help to increase awareness about diagnosis, prevention and treatment of periodontal diseases, in the context of Latin American countries.

BACKGROUND:The objective of this study was to compare a stannous fluoride (SnF2) dentifrice (Colgate TotalSF) stabilized with zinc phosphate with a sodium fluoride control dentifrice for gingivitis and plaque control over a 6-month period.METHODS:One hundred adult participants were enrolled in this study conducted in Chengdu, China. After random assignment and blinding of examiners and patients, enrolled participants received instructions for use of the assigned dentifrice. At 3 visits (baseline and 3 and 6 months), the authors measured various gingival and plaque indexes to determine the clinical efficacy of the stabilized SnF2 dentifrice compared with those of the control fluoride dentifrice (2 groups).RESULTS:Ninety-eight participants completed the study. Both groups (test and control) had statistically significant reductions in gingival inflammation and improvement in plaque control at the 3- and 6-month follow-ups. In addition, the test dentifrice showed statistically significant reductions in all indexes compared with the control dentifrice (P < .001).CONCLUSIONS:This study's results show statistically significantly improved clinical outcomes for reduction of gingival inflammation and improvement in biofilm control over a 6-month period through the use of a SnF2 dentifrice stabilized with zinc phosphate when compared with results with a fluoride control dentifrice.PRACTICAL IMPLICATIONS:This newly formulated dentifrice improves gingival health and plaque control and thereby may aid patients in attaining improved oral health.

OBJECTIVE:The objective of this study was to compare a stabilized stannous fluoride (SnF2) dentifrice with zinc phosphate (Colgate TotalSF) with SnF2 with zinc lactate and control fluoride dentifrices for gingivitis and plaque control over a 6-month period.METHODS:A total of 135 adult participants were enrolled in this study. After randomization and blinding of examiners and patients, enrolled participants were provided instructions for use of assigned dentifrice. At 3 visits (0, 3, and 6 months), various gingival and plaque indexes were collected to determine the clinical efficacy of a stabilized SnF2 dentifrice. These results were compared with a SnF2 with zinc lactate dentifrice and with a control fluoride dentifrice.RESULTS:A total of 135 participants completed the study. All groups reported statistically significant reductions in gingival inflammation and improvement in plaque control at 3- and 6-month follow-up. Both SnF2 dentifrices showed statistically significant reductions in all indexes compared with the control dentifrice (P < .001). However, the test dentifrice showed higher but nonsignificant improvements in plaque and gingival indexes compared with the other SnF2 dentifrice.CONCLUSIONS:This study reports similar efficacy of a test dentifrice to a commercial SnF2-containing dentifrice for plaque control and reduction in gingival inflammation and provides supporting evidence that the test dentifrice maintains its clinical efficacy with change of formulation.PRACTICAL IMPLICATIONS:This newly formulated SnF2 stabilized with zinc phosphate dentifrice may be of benefit to patients in controlling plaque biofilm and gingivitis.

OBJECTIVES:The objective of this single-center, double-blind, parallel-group, randomized six-month clinical study was to evaluate the clinical efficacy of a new Dual Zinc plus Arginine dentifrice (Colgate-Palmolive Co., New York, NY, USA) containing zinc (zinc oxide, zinc citrate) 0.96%, 1.5% Arginine, and 1450 ppm fluoride as sodium fluoride in a silica base in reducing established dental plaque and gingivitis over a six-month period, relative to that of a regular fluoride dentifrice containing 1450 ppm fluoride as sodium fluoride in a silica base (Colgate- Palmolive Co., New York, NY, USA).METHODS:A total of 100 adult male and female subjects from Santo Domingo, Dominican Republic were enrolled in this clinical study. During the baseline visit, the dental examiner clinically measured three gingival parameters (gingival index, gingival severity index, gingival interproximal index) and three plaque parameters (plaque index, plaque severity index, plaque interproximal index). The examining clinician also performed an assessment of the oral soft and hard tissues. All subjects were then assigned a subject identification number in chronological order from 001 to 100 and were randomly assigned to one of two treatment groups following a computer-generated randomization list. They were provided with their assigned dentifrice and an adult, soft-bristled toothbrush for home use, and were instructed to brush twice daily (morning and evening) for one minute with the assigned dentifrice for a period of six months. Subjects returned to the study facility site for their follow-up evaluation of plaque and gingivitis parameters after three and six months.RESULTS:Ninety-six (96) subjects completed the study. At the three-month evaluation, subjects in the Dual Zinc plus Arginine dentifrice group exhibited statistically significant (p < 0.001) reductions in all gingival and plaque parameters relative to subjects in the fluoride dentifrice group. For gingival parameters, reductions were 18.8% for gingival index, 33.3% for gingival severity index, and 19.1% for gingival interproximal index. For plaque parameters, reductions were 11.0% for plaque index, 22.4% for plaque severity index, and 9.8% for plaque interproximal index. At the six-month evaluation, subjects in the Dual Zinc plus Arginine dentifrice group presented continuous statistically significant (p < 0.001) reductions in all three gingival and plaque parameters when compared to the subjects in the fluoride dentifrice group. For gingival parameters, reductions were 26.3% for gingival index, 56.6% for gingival severity index, and 29.2% for gingival interproximal index. For plaque parameters, reductions were 30.1% for plaque index, 61.9% for plaque severity index, and 28.0% for plaque interproximal index after six months of product use.CONCLUSIONS:The overall results of this double-blind clinical study support the conclusion that a Dual Zinc plus Arginine dentifrice containing zinc (zinc oxide, zinc citrate) 0.96%, 1.5% Arginine, and 1450 ppm fluoride as sodium fluoride in a silica base provides significantly greater reduction in dental plaque and gingivitis parameters as compared to a regular fluoride dentifrice containing 1450 ppm fluoride as sodium fluoride in a silica base after three months and six months of product use.

Traditionally, the dental profession has primarily treated periodontitis using a mechanical/surgical, rather than a pharmaceutical, approach. However, based on experiments several decades ago which demonstrated that tetracyclines, unexpectedly, inhibit collagen- and bone-destructive mammalian-derived enzymes (e.g. the collagenases), and through non-antibiotic mechanisms, the concept of host-modulation therapy (HMT) was developed. Accordingly, two drug-development strategies evolved: (i) the development of non-antimicrobial formulations of doxycycline; and (ii) the chemical modification of tetracyclines to eliminate their antibiotic activity but retain (or even enhance) their anti-collagenase properties. Regarding the latter, these chemically modified tetracyclines (CMTs) showed efficacy in vitro, in animal models of periodontal (and relevant systemic) disease, and in preliminary clinical trials on patients with Kaposi's sarcoma (however, at the high doses used, photosensitivity was a significant side-effect). In the first strategy, subantimicrobial-dose doxycycline (SDD) demonstrated safety and efficacy in human clinical trials and was approved by the U S Food and Drug Administration (U S FDA) and in other countries for the treatment of periodontitis (20 mg, twice daily, i.e. once every 12 hours) adjunctive to scaling and root planing, and for chronic inflammatory skin diseases (40-mg sustained-release 'beads'). SDD also showed efficacy in patients with systemic diseases relevant to periodontitis, including diabetes mellitus and arthritis, and in postmenopausal women with local and systemic bone loss. Importantly, long-term administration of SDD, of up to 2 years, in clinical trials did not produce antibiotic side-effects. SDD (and in the future, new HMTs, such as low-dose CMT-3, resolvins and chemically modified curcumins) may shift the paradigm of periodontal therapy from a predominantly surgical approach to the greater use of medicinal/pharmacologic strategies, ultimately to benefit larger numbers of patients.

BACKGROUND:Periodontitis is characterized by microbial infection, inflammation, tissue breakdown, and accelerated loss of alveolar bone matrix. Treatment targeting these multiple stages of the disease provides ways to treat or prevent periodontitis. Certain glycosaminoglycans (GAGs) block multiple inflammatory mediators as well as suppress bacterial growth, suggesting that these GAGs may be exploited as a therapeutic for periodontitis.METHODS:We investigated the effects of a synthetic GAG, GM-0111, on various molecular events associated with periodontitis: growth of Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) pathogenic bacteria associated with periodontitis; activation of pro-inflammatory signaling through TLR2 and TLR4 in mouse macrophage RAW 264.7 cells and heterologously expressed HEK 293 cells; osteoclast formation and bone matrix resorption in cultured mouse pre-osteoclasts.RESULTS:(1) GM-0111 suppressed the growth of P. gingivalis and A. actinomycetemcomitans even at 1% (w/v) solution. The antibacterial effects of GM-0111 were stronger than hyaluronic acid (HA) or xylitol in P. gingivalis at all concentrations and comparable to xylitol in A. actinomycetemcomitans at ≥2% (w/v) solution. We also observed that GM-0111 suppressed biofilm formation of P. gingivalis and these effects were much stronger than HA. (2) GM-0111 inhibited TLR-mediated pro-inflammatory cellular signaling both in macrophage and HEK 293 cells with higher selectivity for TLR2 than TLR4 (IC50 of 1-10 ng/mL vs. > 100 μg/mL, respectively). (3) GM-0111 blocked RANKL-induced osteoclast formation (as low as 300 ng/mL) and bone matrix resorption. While GM-0111 showed high affinity binding to RANKL, it did not interfere with RANKL/RANK/NF-κB signaling, suggesting that GM-0111 inhibits osteoclast formation by a RANKL-RANK-independent mechanism.CONCLUSIONS:We report that GM-0111 inhibits multiple molecular events involved in periodontitis, spanning from the early pro-inflammatory TLR signaling, to pathways activated at the later stage component of bone loss.

In 1983, it was first reported that tetracyclines (TCs) can modulate the host response, including (but not limited to) inhibition of pathologic matrix metalloproteinase (MMP) activity, and by mechanisms unrelated to the antibacterial properties of these drugs. Soon thereafter, strategies were developed to generate non-antibacterial formulations (subantimicrobial-dose doxycycline; SDD) and compositions (chemically modified tetracyclines; CMTs) of TCs as host-modulating drugs to treat periodontal and other inflammatory diseases. This review focuses on the history and rationale for the development of: (a) SDD which led to two government-approved medications, one for periodontitis and the other for acne/rosacea and (b) CMTs, which led to the identification of the active site of the drugs responsible for MMP inhibition and to studies demonstrating evidence of efficacy of the most potent of these, CMT-3, as an anti-angiogenesis agent in patients with the cancer, Kaposi's sarcoma, and as a potential treatment for a fatal lung disease (acute respiratory distress syndrome; ARDS). In addition, this review discusses a number of clinical studies, some up to 2 years' duration, demonstrating evidence of safety and efficacy of SDD formulations in humans with oral inflammatory diseases (periodontitis, pemphigoid) as well as medical diseases, including rheumatoid arthritis, post-menopausal osteopenia, type II diabetes, cardiovascular diseases, and a rare and fatal lung disease, lymphangioleiomyomatosis.

Periodontitis, one of the most common chronic inflammatory diseases afflicting man, is increasingly being recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Non-antimicrobial tetracyclines are known to have inhibitory effects on inflammatory mediators and effector molecules, including cytokines and matrix metalloproteinases (MMPs), associated with both diseases. In this paper, we discuss the evidence that doxycycline and related non-antibiotic chemically modified tetracyclines (e.g., CMT-3) can effectively reduce cytokine (TNF-α, IL-6, and MCP-1) production by human mononuclear inflammatory cells when stimulated either by endotoxin (LPS) or by a complex of C-reactive protein/oxidized LDL cholesterol relevant to the pathogenesis of periodontal disease and ASCVD, respectively. This inhibition by tetracycline compounds appears to be mediated at least in part by a suppression of the phosphorylation/activation of the NFκB cell signaling pathway. We are currently conducting clinical trials on patients who exhibit both diseases, and our preliminary data suggest that virtually all acute coronary syndrome (ACS) patients exhibit moderate-to-severe periodontitis, a higher incidence of this oral inflammatory disease than that seen in the population at large. In other studies, a non-antimicrobial formulation of doxycycline (SDD) has been found to dramatically reduce hsCRP, IL-6 and MMP-9 levels in plasma of ACS patients, and SDD has also been found to significantly increase serum levels of both cardio-protective HDL cholesterol and its core molecule apolipoprotein A-I in ASCVD-vulnerable patients with periodontitis. Our current research suggests that one mechanism involved may be the ability of SDD to inhibit MMP-mediated HDL loss by protecting apolipoprotein A-I from proteinase attack. These pleiotropic mechanisms of non-antimicrobial tetracyclines provide significant therapeutic potential to treat chronic inflammatory diseases including both periodontitis and ASCVD.

BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSION: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.

BACKGROUND Previous studies showed that host modulation therapy (HMT) or topical antimicrobial therapy (TAT) provided significant adjunctive benefits to scaling and root planing (SRP) in the treatment of chronic periodontitis (CP). The purpose of this study was to evaluate a combination therapy involving SRP, HMT, and TAT in the treatment of moderate to severe CP. METHODS A 6-month, randomized, multicenter, placebo-controlled, examiner-masked study was undertaken to evaluate the clinical usefulness of a combination treatment of systemically delivered doxycycline hyclate (HMT; 20 mg, twice a day) plus locally delivered doxycycline hyclate gel (TAT; 10%, in pockets > or =5 mm) in combination with SRP versus SRP plus placebo. Clinical outcomes included mean changes in probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and gingival index (GI) at baseline and at 3 and 6 months. RESULTS In 171 subjects, combination therapy provided significantly greater clinical benefits than control therapy for all clinical measures at 3 and 6 months. In moderate CP (PD of 4 to 6 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.03), BOP (3 months: P <0.02; 6 months: P <0.05), and GI (3 months: P <0.01; 6 months: P <0.03). In severe CP (PD > or =7 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.02), BOP (3 months: P <0.01; 6 months: P >0.05), and GI (3 months: P <0.01; 6 months: P <0.01). CONCLUSION Combination therapy, including SRP, HMT, and TAT, provided significantly greater clinical benefits than SRP alone in the treatment of moderate to severe CP.