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Flurbiprofen treatment of human periodontitis: effect on alveolar bone height and metabolism
Abstract
The effect of the non-steroidal anti-inflammatory drug, flurbiprofen, in reducing periodontal disease activity was assessed in 15 patients with periodontitis. Eight patients received 50 mg flurbiprofen b.i.d. for 2 months, and 7 patients received placebo in this double-blind study. Alveolar bone height was determined using standardized radiography and alveolar bone metabolism was assessed using 99m-Tc-uptake prior to dosing and 2 months later. Radiopharmaceutical uptake was significantly reduced in the alveolar bone of teeth undergoing active bone loss at the start of the study in patients receiving flurbiprofen (p
... NSAIDs have an inhibitory effect on bone destruction in periodontitis processes [157] Dental surgery ...
... However, this effect passes immediately after discontinuation of the drug. Indeed, Jeffcoat et al [157] showed that periodontitis patients treated with flurbiprofen experienced a significant reduction in bone mass loss compared to patients receiving placebo. Unfortunately, the therapeutic effect disappears when the drug is discontinued [154]. ...
Patient pain is a common problem faced by dentists and oral and maxillofacial surgeons. Craniofacial pain may be caused not only by inflammation in the teeth, but also various oral, facial, and nerve-related diseases, as well as tumors. Non-steroidal anti-inflammatory drugs (NSAIDs) constitute the basis of the analgesic ladder. According to the World Health Organisation (WHO), NSAIDs are the first-line drugs in relieving pain and inflammation of oral conditions. NSAIDs have been used in almost every field of dentistry. These drugs are applied in conservative dentistry and endodontics, dental surgery, orthodontics, periodontology, and oral mucosal diseases, as well as head and neck oncology. Some of the NSAIDs exhibit additional therapeutic effects, such as inhibition of nuclear factor kappa B (NF-kappaB) and inducible nitric oxide synthase (iNOS), and reduction of oxidative stress or leukocyte passage to the site of inflammation, which further reduces inflammation in tissues. The topical use of NSAIDs in dentistry is worthy of attention and further research as it will significantly reduce the adverse effects of systemic administration. This article aims to review the preclinical and clinical studies that have supported the role of NSAIDs in dentistry.
... As a complex chronic inflammatory disease (7), periodontitis presents with a non-linear progression, where it has been demonstrated that the disease presents periods of remission, or stability, and progression (8,9). These cycles between stability and progression are still poorly understood, as several factors could be simultaneously playing a role in dysregulating the host immune response. ...
... PGE2 has even been reported to correlate with disease progression (75). The blockade of COX enzymes via use of NSAIDs has demonstrated the ability to inhibit bone resorption in both animal (33)(34)(35)(36) and clinical studies (9,37). The effects of these drugs, however, did not remain after withdrawal of the drug (29). ...
Periodontitis is a chronic inflammatory condition initiated by the accumulation of bacterial biofilm. It is highly prevalent and when left untreated can lead to tooth loss. The presence of bacterial biofilm is essential for the initiation of the inflammatory response but is not the sole initiator. Currently it is unknown which mechanisms drive the dysbiosis of the bacterial biofilm leading to the dysregulation of the inflammatory response. Other players in this equation include environmental, systemic, and genetic factors which can play a role in exacerbating the inflammatory response. Treatment of periodontal disease consists of removal of the bacterial biofilm with the goal of resolving the inflammatory response; however, this does not occur in every case. Understanding the way the inflammatory response does not return to a state of homeostasis has led investigators to consider both systemic and local pharmacological interventions. Nonetheless, a better understanding of the impact that genetics and environmental factors may have on the inflammatory response could be key to helping identify how inflammation can be modulated therefore stopping the destruction of the periodontium. In this article, we will explore the current evidence associating the microbial dysbiosis and the dysregulation of the immune response, potential mechanisms or pathways that may be targeted for the modulation of the inflammatory response, and discuss the advantages and drawbacks associated with local and systemic inflammatory modulation in the management of periodontal disease. This information will be valuable for those interested in understanding potential adjunct methods for managing periodontal diseases, but not limited to, dental professionals, clinical researchers and the public at large.
... In two separate studies, a significant reduction in bone loss was observed when adult human subjects with moderate to severe periodontitis were treated topically with toothpaste containing 1% w/w of FBP or systemically with 50 mg of FBP, both twice daily. This suggested the influence of FBP on bone metabolism [15,16]. FBP blocks the cyclooxygenase enzyme which causes inflammation and pain [15]. ...
... FBP blocks the cyclooxygenase enzyme which causes inflammation and pain [15]. The drug is used for not only relieving pain in periodontitis, but also for slowing the disease process [16]. Looking at the potential benefits of the described drugs, it is worthwhile to attempt exploring the combination of the duo in the treatment of localized oral cavity disease (such as periodontitis). ...
A new high-performance liquid chromatographic (HPLC) method for determination of triclosan (TCS) and flurbiprofen (FBP) was successfully developed and validated at a single wavelength. The method involves extraction of the targeted drugs from nanogels and simulated saliva by using methanol as the extractant. The Agilent ZORBAX SB-C18 column (5 μm, 4.6 × 250 mm) was used for the chromatographic separations. The effects of various parameters were extensively evaluated and optimized. The optimal HPLC conditions were acetonitrile and 0.001 M citric acid (90:10, v/v) with a pH of 3.24 as the mobile phase, at a 0.3 mL/min flow rate under isocratic elution mode. Excellent sensitivity and specificity were achieved by ultraviolet (UV) detection at 242 nm. The method also demonstrated excellent linearity within the test range of 10–100 μg/mL with the correlation coefficient (R²) of 0.9998 for both the analytes. The practical applicability of the method was demonstrated by recovering TCS and FBP from nanogels and simulated saliva. The recovery of the analytes from the nanogels and the spiked simulated saliva samples was in the range of 97–98% and 96–99%, respectively, and their respective relative standard deviation (RSD) was less than 0.9% in both cases. System suitability parameters were found to be within acceptable limits. The method is simple, specific, and precise, and to the best of our knowledge, it is the first reported validated quantitative HPLC method for the concurrent determination of TCS and FBP in a pharmaceutical dental product. The method can be useful in the routine quality control analysis of dental formulations with TCS and FBP contents or products with a similar composition.
... Additionally, compared to the flurbiprofen-treated group, more tooth locations with bone loss were found in the placebo group. 5 ...
... Some earlier studies have shown that NSAIDs may have a therapeutic role in the process. Jeffcoat et al. [66] recruited 15 patients with active moderate-to-severe periodontitis and administered 50 mg b.i.d. flurbiprofen or placebo for 2 months. ...
Periodontitis is the sixth most prevalent chronic disease globally and places significant burdens on societies and economies worldwide. Behavioral modification, risk factor control, coupled with cause-related therapy have been the “gold standard” treatment for managing periodontitis. Given that host inflammatory and immunological responses play critical roles in the pathogenesis of periodontitis and impact treatment responses, several adjunctive strategies aimed at modulating host responses and improving the results of periodontal therapy and maintenance have been proposed. Of the many pharmacological host modulators, we focused on non-steroidal anti-inflammatory drugs (NSAIDs), due to their long history and extensive use in relieving inflammation and pain and reducing platelet aggregation. NSAIDs have been routinely indicated for treating rheumatic fever and osteoarthritis and utilized for the prevention of cardiovascular events. Although several efforts have been made to incorporate NSAIDs into the treatment of periodontitis, their effects on periodontal health remain poorly characterized, and concerns over the risk–benefit ratio were also raised. Moreover, there is emerging evidence highlighting the potential of NSAIDs, especially aspirin, for use in periodontal regeneration. This review summarizes and discusses the use of NSAIDs in various aspects of periodontal therapy and regeneration, demonstrating that the benefits of NSAIDs as adjuncts to conventional periodontal therapy remain controversial. More recent evidence suggests a promising role for NSAIDs in periodontal tissue engineering and regeneration.
... Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the conversion of arachidonic acid to the prostaglandin series of metabolites. The resultant prostaglandins themselves have been implicated in both bone resorption and bone formation [18,19]. Prostaglandin levels are elevated in inflamed tissues, and prostaglandin E 2 reportedly causes bone resorption in vitro [20,21]. ...
Purpose:
Some systemic conditions, especially diabetes mellitus (DM), adversely affect dental implant success. This study aimed to investigate the effects of ibuprofen-loaded TiO2 nanotube (ILTN) dental implants in alloxan-induced diabetic rabbits.
Methods:
Twenty-six New Zealand white rabbits were treated with alloxan monohydrate to induce DM. At 2 weeks following DM induction, 3 types of implants (sandblasted, large-grit, and acid-etched [SLA], ILTN, and machined) were placed into the proximal tibia in the 10 rabbits that survived following DM induction. Each type of implant was fitted randomly in 1 of the holes (round-robin method). The animals were administered alizarin (at 3 weeks) and calcein (at 6 weeks) as fluorescent bone markers, and were sacrificed at 8 weeks for radiographic and histomorphometric analyses.
Results:
TiO2 nanotube arrays of ~70 nm in diameter and ~17 μm in thickness were obtained, and ibuprofen was loaded into the TiO2 nanotube arrays. A total of 26 rabbits were treated with alloxan monohydrate and only 10 rabbits survived. The 10 surviving rabbits showed a blood glucose level of 300 mg/dL or higher, and the implants were placed in these diabetic rabbits. The implant stability quotient (ISQ) and bone-to-implant contact (BIC) values were significantly higher in the ILTN group (ISQ: 61.8, BIC: 41.3%) and SLA group (ISQ: 62.6, BIC: 46.3%) than in the machined group (ISQ: 53.4, BIC: 20.2%), but the difference in the BIC percentage between the SLA and ILTN groups was not statistically significant (P=0.628). However, the bone area percentage was significantly higher in the ILTN group (78.0%) than in the SLA group (52.1%; P=0.000).
Conclusions:
The ILTN dental implants showed better stability (ISQ) and BIC than the machined implants; however, these values were similar to the commercially used SLA implants in the 2-week diabetic rabbit model.
... FLB belongs to non-steroidal antiinflammatory drugs (NSAIDs). Studies have revealed evidence which indicated that supplementing periodontitis treatment with NSAIDs like FLB can improve the outcome of the therapy (Jeffcoat et al., 1988;Ribeiro et al., 2012). However, clinical data that reveal the effect of treatment of periodontitis with TCS and FLB combination is lacking. ...
Purpose
To evaluate therapeutic effectiveness of antibacterial triclosan (TCS) and anti-inflammatory flurbiprofen (FLB)-loaded nanogels system in ligature-induced experimental periodontitis in rats.
Methodology
A total of 72 Sprague–Dawley rats were used in this study. Four groups (n=18 each) were randomly created: Group 1 – neither subjected to experimental periodontitis nor to any treatment; Group 2 – subjected to experimental periodontitis but not treated; Group 3 – subjected to experimental periodontitis and then treated with the developed nanogels; Group 4 – subjected to experimental periodontitis and then placed on a mixture of pure TCS and FLB treatment. The experimental periodontitis was induced on the lower incisors by applying a ligature which was kept for 14 days. Treatment was done for 7 days, and sampling was done at 7, 14, and 28 day of the post-induction experimental period. Morphometric analysis was conducted to assess the clinical outcomes and healing effect.
Results
The morphometric findings showed that the group treated with the developed TCS and FLB-loaded nanogels recovered better and faster than a mixture of pure TCS and FLB. At 28 day of the experimental period, there was no significant difference (p>0.05) between the baseline control group and the nanogels treated group.
Conclusions
The developed TCS and FLB-loaded nanogels was found to be effective in the treatment of experimental periodontitis in rats. The used experimental periodontitis model was found to be simple and easily reproducible.
... Finally, patient compliance to the duration and frequency of taking medication should be considered. [113] 2400 mg/day Bone loss around implants (6 m) [91,92] 1200 mg/day Increases bone resorption [90] Naproxen 1000 mg/day Bone defect fill and resorption (9 m) [114] Flurbiprofen 100 mg/day Inhibits periosteal bone formation Inhibits bone resorption [115] Enolic acid Piroxicam 20 mg/day No effect on BMD and fracture healing [116] ...
Abstract The failure of remodeling process that constantly regenerates effete, aged bone is highly associated with bone nonunion and degenerative bone diseases. Numerous studies have demonstrated that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) activate cytokines and mediators on osteoclasts, osteoblasts and their constituent progenitor cells located around the remodeling area. These cells contribute to a complex metabolic scenario, resulting in degradative or synthetic functions for bone mineral tissues. The spatiotemporal effects of aspirin and NSAIDs in the bone remodeling are controversial according the specific therapeutic doses used for different clinical conditions. Herein, we review in vitro, in vivo, and clinical studies on the dose-dependent roles of aspirin and NSAIDs in bone remodeling. Our results show that low-dose aspirin (
... Various anti-inflammatory drugs, such as NSAIDs, 17 Aspirin at higher anti-inflammatory doses has shown a beneficial effect on periodontal inflammation. 5 As high doses have shown many side-effects, attempts have been made to evaluate the effect of low-dose aspirin on periodontal diseases. ...
Aim
In the present study, we evaluated the effect of systemic long‐term, low‐dose aspirin on the periodontal status and gingival crevicular fluid (GCF) concentrations of aspirin‐triggered lipoxins (ATL) and soluble CD14 (sCD14).
Methods
The study group consisted of 45 patients who were on long‐term, low‐dose aspirin therapy, and the control group included patients not on aspirin therapy. Mean bleeding index, plaque index (PI), probing depth (PD), and clinical attachment loss (CAL) were recorded. GCF samples were analyzed for concentrations of ATL, and sCD14 using enzyme‐linked immunosorbent assay method.
Results
The means of PI, PD, and CAL were higher for the control group compared to the study group. The mean concentration of ATL was significantly higher for the study group (49.13 ± 37.39 ng/mL). The mean concentration of sCD14 was higher in the control group (5.75 ± 3.91 μg/mL). There was a negative correlation in the study group between concentrations of ATL with PD (r = −0.54) and CAL (r = −0.123). There was a positive correlation between sCD14 and CAL (r = 0.047) in the study group. A negative correlation was also observed between concentrations of sCD14 and ATL (r = −0.134) in the study group.
Conclusion
The results indicate better periodontal status among long‐term aspirin users compared to non‐aspirin users.
... The on-site generation and release of prostaglandins (PGs) [4] and arachidonic acid metabolites [5] are mainlyresponsible for periodontal destruction [6]. Non-steroidal antiinflammatory drugs (NSAIDs) have delivered promising results in periodontal treatment due to their ability to decrease the inflammatory destruction [7][8][9]. NSAIDs suppress the formation of eicosanoids by blocking the cyclooxygenase (COX) enzyme systems which converts arachidonic acid to the individual metabolites [10]. These metabolites are responsible for periodontal destruction [11]. ...
... Attempts at elimination of infectious agents do not often represent a definitive therapy in periodontitis; necessitating the administration of more sophisticated biological treatment modalities. It was established in the 1980's that modulation of the host response with cyclooxygenase inhibitors (61,62,97,98,(132)(133)(134)(135) was effective in halting the progression of periodontitis. However, the side effects of chronic long term use of cyclooxygenase inhibitors were significant creating a poor risk/benefit ratio, and the use of these drugs for the routine treatment of periodontitis was abandoned. ...
Inflammation is a highly organized event impacting upon organs, tissues and biological systems. Periodontal diseases are characterized by dysregulation or dysfunction of resolution pathways of inflammation that results in failure to heal and in a dominant chronic, progressive, destructive and predominantly unresolved inflammation. The biological consequences of inflammatory processes may be independent of the etiological agents, such as trauma, microbial organisms and stress. The impact of the inflammatory pathological process depends upon the tissues or organ system affected. Whilst mediators are similar, there is tissue specificity for the inflammatory events. It is plausible that inflammatory processes in one organ could directly lead to pathologies in another organ or tissue. Communication between distant parts of the body and their inflammatory status is also mediated by common signaling mechanisms mediated via cells and soluble mediators. This review focuses on periodontal inflammation, its systemic associations and advances in therapeutic approaches based on mediators acting through orchestration of natural pathways to resolution of inflammation. We also discuss a new treatment concept in which natural pathways of resolution of periodontal inflammation can be used to limit systemic inflammation and promote healing and regeneration.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
... In individuals with periodontitis, twice-daily rinsing with 0.1% ketorolac was at least as effective in preserving alveolar bone as systemic flurbiprofen (50 mg twice daily). Studies utilizing the beagle model of periodontitis have shown that topically administered ketoprofen, flurbiprofen, and piroxicam can significantly reduce bone loss and slow the progression of periodontitis (Jeffcoat et al., 1988; Howell et al., 1991; Paquette et al., 1997). Although in vitro and in vivo studies have demonstrated the benefits of topical NSAIDs in the treatment of periodontitis, little is known about the mechanism by which these agents penetrate the oral epithelium. ...
The aim of the study was to design and evaluate mucoadhesive buccal patches of naproxen for local treatment of pain and inflammations of the oral cavity. Buccal patches were fabricated by solvent casting technique using hydroxypropylmethylcellulose E4M, Eudragit RLPO, ethyl cellulose, polyvinylpyrrolidone, methyl cellulose, hydroxypropylcellulose and chitosan either alone or as mixtures. Ten formulations were subjected to various evaluation parameters. Based on the evaluation of the results, it was concluded that Formula-2 (F-2) containing 1 % HPMC and 0.5 % Eudragit RLPO showed good mucoadhesive strength (47.07 g), promising controlled and complete drug release within 210 min, highest residence time (120 min in vivo and 125 min in vitro), acceptable elasticity (13.834 %mm-2), swelling index (85.4 % in 15 min) and surface pH (6.5). Accordingly, F-2 could be selected as the best formula among the formulations studied and was subject to further in vivo study. The obtained in vivo results indicate that the concentration of naproxen in the oral cavity was maintained above 4 μg/mL for a period of 120 min, which was within and
higher than the reported range of the IC50 of naproxen. A significant in vitro/in vivo correlation was obtained (R2 = 0.9787). The results indicate that the mucoadhesive buccal patches of naproxen may be a good choice to bypass the undesirable systemic side effects and can be proposed as a new therapeutic tool against dental and buccal inflammatory diseases and disturbs.
... Maintenance of osseointegration and a marginal alveolar bone levels are therefore pivotal for predictable and long-term performance of implant supported prostheses (152). The inhibition of PG production with oral administration of several NSAIDs, including flurbiprofen (153,154), naproxen (155) and meclofenamate sodium (156), can reduce the rate of bone loss associated with periodontal disease. Although it might be tempting to assume that NSAIDs can have a similar influence on the bone supporting dental implants, resulting in a 'bone sparing effect' (157), several reports in the medical literature have suggested that NSAIDs can delay bone fracture healing (158,159) and impair bone in growth in orthopaedic implants (160,161). ...
... 3 The powerful inhibitory effect of aspirin on cyclo-oxygenase metabolites, including PGE 2 , has resulted in many studies on the effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on periodontal diseases. [4][5][6] It has been demonstrated that people taking aspirin at higher doses had reduced gingival indices, probing depth and attachment loss compared to controls. 7 In humans, systemic administration of NSAIDs has been demonstrated to reduce gingival inflammation in experimental gingivitis and halt the progression of periodontal bone loss in patients with periodontitis. ...
Pharmaceutical inhibition of host response pathways may be an adjunctive or alternative strategy for treating periodontal diseases. In addition to inhibition of prostaglandin synthesis, aspirin is known to modify the action of cyclo-oxygenase, changing its activity to a lipoxygenase and leading to formation of lipoxins which have a proresolving effect. This study evaluated the periodontal attachment level of subjects on long-term low dose aspirin therapy.
Oral hygiene index simplified, clinical attachment loss and bleeding index were recorded for 162 subjects who were on long-term (>6 months) low dose (75 mg and 150 mg) aspirin therapy (study group) and 146 subjects not taking the drug (control group).
Mean clinical attachment loss was 2.38 ± 0.49 mm in the control group and 2.01 ± 0.69 mm in the study group. The difference was statistically significant at p < 0.001. Correlation analysis suggested that there was a negative correlation between clinical attachment loss and duration of aspirin intake but the clinical attachment loss was not significantly different in the two dosage groups.
The results of this study suggest that low dose aspirin may reduce the risk of periodontal attachment loss. This hypothesis needs to be tested by larger sample sized prospective cohort studies.
... Studies have shown that the adjunctive use of either systemic or local NSAIDs provides additional reductions in both gingival inflammation and alveolar bone resorption. 29,30 NSAIDs can be of therapeutic value in treating periodontal disease because of their ability to interfere with the arachidonic acid metabolism, thereby inhibiting the inflammatory process. Among the various drugdelivery methods used, chitosan, a bio-adhesive polymer, has been proposed due to its favorable properties, such as biocompatibility and biodegradability. ...
Aim: Local drug delivery is a non-surgical method in the treatment of periodontitis. Different chemotherapeutic agents are used for local drug delivery; one such agent is tetracycline, a broad-spectrum antibiotic. Recent studies have also shown that the use of non-steroidal anti-inflammatory drugs reduces pro-inflammatory cytokines and acts as host modulator. Thus, an attempt was made to compare and evaluate the efficacy of tetracycline alone and in combination with diclofenac sodium as a local drug delivery.
Methods: A total of 36 sites with chronic periodontitis were divided into three groups with 12 sites each (i.e. group A, antibiotics alone; group B, antibiotics in combination with non-steroidal anti-inflammatory drugs; and group C, control group). For all the groups, the following parameters (plaque index, papillary bleeding index, probing pocket depth, and microbial analysis) were assessed and statistically analyzed.
Results: The antibiotic and non-steroidal anti-inflammatory drug combination group showed a statistically-significant improvement in clinical parameters and a shift in microbial flora when compared to the group with antibiotics alone. However, the control group failed to show any statistically-significant improvement.
Conclusion: Antibiotics in combination with non-steroidal anti-inflammatory drugs are more efficient than using antibiotics alone as local drug delivery for the treatment of periodontal pockets
... A number of papers have reported a reduction in the amount of alveolar bone loss or gingival inflammation compared to control groups. [47][48][49][50][51][52] However, widespread use of NSAIDs has not been widely reported, perhaps due to minimal clinical advantage produced, reports demonstrating no or little effect or side effects that outweigh the benefits. ...
Non-surgical removal of plaque and calculus has been part of the initial phase of the management of patients with gingivitis and periodontitis for decades. It consists of patient motivation and oral hygiene instruction as well as mechanical removal of supra and subgingival plaque deposits. The purpose of this review was to assess recent changes. The article reports on changes in our understanding of plaque as a biofilm, developments in patient plaque control, chemical plaque control and scaling instruments. It also comments on full-mouth disinfection, the use of lasers and host modulation. Modern technology has made removal of microbial deposits by the patient and dental professionals more efficient. However, other advancements need to be used in conjunction with mechanical debridement at this time.
... This is due, in part, to a positive effect on osteoclastogenesis by promotion of the expression of RANKL and the inhibition of osteoprotegerin (OPG) (Raisz, 1999; Horowitz et al., 2005 ). Non-steroidal antiinflammatory drugs (NSAIDs), which interfere with PGE 2 synthesis , may slow the rate of periodontal destruction (Williams et al., 1985Williams et al., , 1989 Jeffcoat et al., 1988; Weber et al., 1994; Paquette et al., 1997; Salvi and Lang, 2005). Thus, it seems that inhibitors of prostaglandin synthesis (viz., NSAIDs) would be likely to promote bone regeneration. ...
Various strategies have been developed to promote bone regeneration in the craniofacial region. Most of these interventions utilize implantable materials or devices. Infections resulting from colonization of these implants may result in local tissue destruction in a manner analogous to periodontitis. This destruction is mediated via the expression of various inflammatory mediators and tissue-destructive enzymes. Given the well-documented association among microbial biofilms, inflammatory mediators, and tissue destruction, it seems reasonable to assume that inflammation may interfere with bone healing and regeneration. Paradoxically, recent evidence also suggests that the presence of certain pro-inflammatory mediators is actually required for bone healing. Bone injury (e.g., subsequent to a fracture or surgical intervention) is followed by a choreographed cascade of events, some of which are dependent upon the presence of pro-inflammatory mediators. If inflammation resolves promptly, then proper bone healing may occur. However, if inflammation persists (which might occur in the presence of an infected implant or graft material), then the continued inflammatory response may result in suboptimal bone formation. Thus, the effect of a given mediator is dependent upon the temporal context in which it is expressed. Better understanding of this temporal sequence may be used to optimize regenerative outcomes.
... Previous studies have demonstrated that inhibition of prostaglandin production with oral administration of several NSAIDs including flurbiprofen 11,12 , naproxen 13 and meclofenamate sodium 14 can reduce the rate of bone loss associated with periodontal disease in patients. Although it might be tempting to assume that NSAIDs can have a similar influence on the bone supporting dental implants resulting in a 'bone sparing effect' 15 , several reports in the medical literature have suggested that NSAIDs can delay bone fracture healing 16,17 , and impair bone ingrowth into orthopaedic implants 18,19 . ...
This randomised double-blind placebo-controlled trial was carried out to investigate the effect of a one-week post-operative course of 600 mg of ibuprofen taken four times a day on marginal bone level around dental implants.
A total of 61 patients were allocated to the ibuprofen (31 patients) or placebo group (30 patients). Overall, 132 implants were inserted, 67 implants in the ibuprofen group and 65 implants in the placebo group. Preparation of the implant sites was carried out with an intermittent drilling sequence adapted to the fixture diameter and the local bone quality according to the Astra Tech implant installation guide. The primary outcome measure was the change in marginal bone level around dental implants from the baseline (2 weeks post-placement) to the 3- and 6-month radiographic examinations. The paralleling technique and a film holder coupled to a beamaiming device were used to take the periapical radiographs. Measurement of changes in bone level was made using a viewing box and x8 magnifier.
Two patients from the ibuprofen group were unable to complete the prescribed course of ibuprofen owing to a minor self-reported stomach upset. A patient from the control group did not attend any of the scheduled appointments following implant placement. A total of three patients dropped out. All implants survived in either group during the 6-month observation period. The mean marginal bone level changes from the baseline were (-0.33 mm) at the 3-month and (-0.29 mm) at the 6-month follow-up for the ibuprofen group while the corresponding values for the placebo group were (-0.12 mm) and (-0.30 mm). There were no statistically significant differences between groups for mean marginal bone level changes at 3 months (P = 0.27) or 6 months (P = 0.97).
Administration of a short course of systemic ibuprofen for post-operative pain management subsequent to implant placement may not have a significant effect on the marginal bone around dental implants in the early healing period.
... Many host modulatory therapies have been implemented to target the host defenses in periodontal infections. Multiple studies have shown significant clinical improvement and reduction of alveolar bone destruction by modulating arachidonic acid metabolites [135][136][137] and matrix metalloproteinases (MMPs) [138,139]. Successful attempts have been made to alter osteoclast activity through bisphosphonates [140,141] and a novel vacuolar ATPase [142]. ...
Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The innate and acquired immune systems are critical for the proper immune response. LPS, an outer membrane constituent of periodontal pathogenic bacteria, stimulates the production of inflammatory cytokines IL-1beta, TNFalpha, IL-6 and RANKL either directly or indirectly. In LPS-stimulated cells, the induction of cytokine expression requires activation of several signaling pathways including the p38 MAPK pathway. This review will discuss the significance of the p38 MAPK pathway in periodontal disease progression and the potential therapeutic consequences of pharmacological antagonism of this pathway in the treatment of periodontal diseases.
Relevance. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed in dental practice to relieve pain and swelling. This study reviews information on NSAIDs, with a particular focus on those aspects that are relevant to the practice of dentistry. Materials and methods. A systematic literature search was conducted, which included studies dating from 1970 to June 2021. The search in the electronic databases e-LIBRARY.ru, Embase, Pubmed and Medline identified the studies. Articles were reviewed by meeting the inclusion and non-inclusion criteria. Results. Initially, the electronic search identified 589 studies. After reviewing the titles and abstracts, 69 potentially relevant studies were subject to full-text evaluation. Of these, 34 studies were excluded based on study design, research question, or lack of numerical data on all variables to be assessed in this study, so 35 studies with a detailed list of such data could be included in the quantitative comparison. Conclusion. The use of non-steroidal anti-inflammatory drugs may alter the inflammatory response in the treatment of oral diseases. The conducted studies have brought up questions about the effectiveness and alternative ways of NSAID delivery in dentistry, namely, dispersible formulation.
Objectives
The non-steroidal anti-inflammatory drug etoricoxib is the most highly selective inhibitor of cyclooxygenase-2 available (344:1) and has been approved for postoperative pain therapy following dental interventions in Europe. At clinically relevant doses it has been reported to only have marginal effects on the velocity of orthodontic tooth movement (OTM). Its effects on associated dental root resorptions, osteoclastogenesis, trabecular number in the alveolar bone and periodontal bone loss during OTM, however, have not yet been investigated.
Material and Methods
40 male Fischer344 rats were divided into four groups: 1.5 ml tap water/day p.o. (control, 1), additional 7.8 mg/kg/day etoricoxib (normal dose) for three (2) or seven (3) days/week and 13.1 mg/kg/day (high dose) for seven days/week, respectively (4). After a week of premedication, OTM in anterior direction of the first left upper molar was performed for 28 days by means of a nickel-titanium coil spring (0.25 N). We quantified OTM-associated dental root resorptions, osteoclastogenesis, trabecular number and periodontal bone loss by histomorphometrical, histochemical and μCT analyses of the disected tooth-bearing upper jaw sections.
Results
After 28 days of OTM, associated tended reduction of trabecular number seemed to be slightly alleviated by high doses of etoricoxib, whereas no significant other etoricoxib effects in the doses administered could be detected regarding OTM-induced or -associated dental root resorptions, osteoclastogenesis or periodontal bone loss.
Conclusions
Dental root resorptions, osteoclastogenesis and periodontal bone loss during OTM in rats were not significantly affected by etoricoxib in the clinically relevant dosages investigated with only a slight inhibitory effect on bone remodelling to be expected at high dosages. Etoricoxib is therefore not suitable for the prevention of these detrimental effects, but could be a suitable analgesic during OTM, as it has been reported not to affect tooth movement.
Current medical healthcare has no sufficient innovative drug delivery formulations for treating patients with alveolar osteitis. This study presents a portion of research conducted to design, fabricate, and characterize systems for the treatment of alveolar osteitis. The results demonstrate that intra-alveolar formulations can be designed to function as drug carriers, facilitate wound dressing, and promote tissue regeneration. Our aim was to design cone-shaped implants made of microcrystalline chitosan filled with sodium meloxicam, i.e., a nonsteroidal anti-inflammatory agent. SEM analysis revealed the porous structure and monophasic characteristic of the formulation. Moreover, textural analysis demonstrated the effect of different factors (shape, hydration, addition of an active substance) on the hardness, springiness and cohesiveness of the studied systems. The active substance was released in a two-phase process. In vitro biocompatibility tests performed according to ISO 10993-5 confirmed the lack of cytotoxicity of the tested formulations. The designed formulations did not stimulate human THP1-XBlue™ monocytes to activate the transcription nuclear factor NF-κB, which ensures that the performed systems do not induce local inflammation. These initial results indicate that the innovative sodium meloxicam release system can improve safety and efficacy in clinical settings.
Bacterial Etiology of Periodontial Disease Activation of the Innate Immune Response and Periodontal Disease Activation of the Adaptive Immune Response and Periodontal Disease Interactions between the Innate and Adaptive Immune Responses Inflammation-Induced Osteoclastogenesis Coupled Bone Formation in Periodontal Disease References
As the United States population ages, people will be taking more medications which may benefit their general health but not necessarily their periodontal health. The effects of medications have been grouped into six categories as follows: behavioral alteration of oral hygiene methods, alteration of plaque composition, effect on gingival tissues, effect on alveolar bone, effect on gingival crevicular fluid, and effect on salivary flow. Although most medications discussed in this paper increase the risk for periodontal disease, a few may actually decrease the risk. These include the effect of Phenytoin on alveolar bone, the antibacterial effect of antibiotics, the anticollagenolytic effects of tetracyclines, and the effect of non-steroidal anti-inflammatory drugs on decreasing alveolar bone resorption. J Periodontol 1996;67:1055–1059.
Chemistry Flurbiprofen, a non steroidal anti-inflammatory drug is a phenylalkanoic acid derivative (2-2-Fluoro-4-biphenyl 4-yl, propionic acid) having molecular weight 244.3 g/mol with molecular formula of C 15 H 13 FO 2 [1-3]. Flurbiprofen is commercially available as a racemate blend of (+) Sand (-) R-enantiomers. The enanteomeric form of the drug has potentially developing role in the treatment of Alzheimer's disease and metastatic prostate cancer with anti-inflammatory activity [4-5]. Davis et al in 2000 observed the significant stimulatory effects on intestinal permeability in rats followed single oral doses of Flurbiprofen as racemate and enantiomer [6] (Figure 1). Pharmacokinetics Flurbiprofen completely absorbed after oral administration [7] with peak plasma levels occurring at 1 hour Plasma concentration is related to dosage in the range 15 to 150 mg and peak plasma concentration is about 12μg/ml after a 100 mg dose and is usually attained 1.5 to 3 hours after ingestion [8,9]. Flurbiprofen is 99% bound to human serum albumin [10,11]. Flurbiprofen undergoes rapid oxidative metabolism and is excreted primarily in the urine as both glucuronide and sulphate conjugates and approx 20% of drug eliminated unchanged [10,11]. There are no known active metabolites in humans and there is no evidence of dose dependent alterations of pharmacokinetics or of drug accumulation in plasma after multiple dose administration. The elimination half-life is about 3.5 hours during repeated doses [12]. Gastric emptying rate is found notably higher in fed state [13]. Flurbiprofen is a CYP2C9 substrate and modification of the Dose adjustments are recommended when given with inhibitor of CYP2C9 agents [14]. Flurbiprofen gastrointestinal tolerance is considered better than other NSAIDs i.e. indomethacin and aspirin, and comparable to naproxen and ibuprofen. It has shown no problematic or irreversible hepatotoxic, carcinogenic or teratogenic effects. Hypertensive and renal effects are probably similar to other NSAIDs.
Non-steroidal anti-inflammatory drugs (NSAIDs) act against not only inflammation but also down-regulation of bone remodeling. The inhibitory mechanisms of their action on bone remodeling are still unclear. We hypothesized that an NSAID, diclofenac, down-regulates osteoclast differentiation and activation via inhibition of the translocation of phosphorylated nuclear factor kappa B (NFκB). When osteoclasts prepared from mouse hematopoietic stem cells were treated with diclofenac, tartrate-resistant acid phosphatase-positive multinucleated cells decreased in a concentration-dependent manner, leading to the abolition of osteoclastic bone resorption. Levels of cathepsin K transcripts, an osteoclastic resorption marker, were down regulated. Diclofenac induced the accumulation of the inhibitor of kappa B in cytosol, which led to suppression of the nuclear translocation of NFκB and phosphorylated NFκB. These results suggest that the novel mechanism of diclofenac for bone remodeling is associated with phosphorylated NFκB reduction, which regulates osteoclast differentiation and activation.
A double-blind, placebo-controlled trial was conducted to determine the effects of the nonsteroidal anti-inflammatory drug Naprosyn® (naproxen) on gingival inflammation. The enrollment of 114 patients provided 102 patients valid for efficacy evaluation, each having a mean gingival index (GI) score of 1.5 or greater at test-teeth sites. Patients were given oral Naprosyn 500 mg b.i.d. or placebo for 30 days. At 28 d, full-mouth prophylaxis was performed. Gingival index, modified sulcular bleeding index (SBI), and plaque index (PI) scores were taken at baseline, at 28 d, and at 30 d. When the 28-d index measurements were compared to baseline, the drug had no significant effect on plaque index scores or gingival inflammation. Statistically, Naprosyn enhanced the resolution of gingival inflammation following removal of microbial plaque. Thus, although this drug does not suppress the inflammation-inducing properties of plaque, Naprosyn may enhance recovery following plaque removal.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing computerized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorption. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of human patients are limited. Further research is required to confirm or refute the findings of this systematic review.
Previous studies revealed that interleukin-1beta (IL-1beta) was detectable in gingival crevicular fluid (GCF) of patients with periodontitis, and the level was increased in level in gingival tissue extracts of active periodontal disease sites (defined as attachment loss > or = 2.5 mm over the preceding 2 months) compared to inactive sites or healthy sites. The present study evaluated the relationship of IL-1beta level in GCF and periodontal disease status. GCF was collected with Periopaper strips from 34 disease-active and 45 disease-inactive teeth in 11 untreated periodontitis patients and from 60 teeth in 15 healthy control subjects. Disease activity was defined as attachment loss of > or = 2.5 mm in at least one site of a tooth as determined by sequential probing. The absorbed GCF volume was determined using a Periotron 6000 and the crevicular IL-1beta level was determined using IL-1beta monoclonal antibody (Otsuka Pharmaceutical, Japan). IL-1beta was below the detection level of the assay (6 pg/ml) in the healthy control group but was detected in most teeth of the periodontitis group. However, disease-active teeth had higher IL-1beta level (Mann-Whitney U-test, p < 0.05) than disease-inactive teeth (mean total IL-1beta of 5.89 +/- 7.88 pg/tooth and 1.72 +/- 2.28 pg/tooth; mean concentration of 1.6 +/- 2.5 ng/ml and 0.6 +/- 0.83 ng/ml, respectively). The level of IL-1beta showed no correlation with probing depth, but had significant correlation (p < 0.05) with the extent of attachment loss. This study suggests that the level of IL-1beta in GCF may have a predictive value for determining active and inactive periodontal status.
The present study was designed to examine whether systemic administration of a bisphosphonate, risedronate, could prevent alveolar bone resorption in rats with experimental periodontitis. On Day 1, an elastic ring was placed around the neck of the right mandibular 1st molar to induce inflammatory periodontitis. The animals were given daily injections of either 0.9% NaCl (control group), or 0.8, 1.6 or 3.2 Öoles/kg (s.c.) of risedronate (experimental groups) from Days 1 to 7, and were killed on Day 8. Histological examinations and determination of bone mineral density in the interdental area between the 1st and 2nd molars with an image analyzer revealed that the presence of the elastic ring induced a loss of attachment and bone resorption in the control group. Vigorous bone resorption, with appearance of a large number of osteoclasts, was observed in the interdental and bifurcation areas. In the experimental groups, however, the resorption of alveolar bone and the loss of bone mineral content in these areas were prevented in a dose-dependent fashion, especially at doses of 1.6 and 3.2 Ömoles/kg. Many osteoclasts were detached from the surface of the alveolar bone and had degenerated appearances, such as rounded shapes, loss of polarity and pyknosis. These results suggest that administration of risedronate is effective in preventing bone resorption in periodontitis.
Samples of gingival crevicular fluid (GCF) were harvested from sites manifesting features characteristic of active disease including inflammation, periodontal attachment loss, and radiographic signs of alveolar bone destruction in untreated patients with advanced periodontitis. The presence and concentrations of interleukin-lα (IL-lα) and interleukin-1β (IL-1β) were measured using ELISAs specific for these cytokine molecules. IL-lα and/or IL-1β were identified in the GCF of 15 of 15 patients having untreated periodontitis. Ninety percent (71 of 79) of the sites tested contained measurable amounts of IL-l. with IL-lβ as the more frequently occurring form. IL-lα levels ranged from 0.23 nM to 13.9 nM in the GCFs. IL-1β levels were between 0.04 nM and 5.28 nM. Marked reductions of total IL-1 levels were observed following effective treatment. Both forms of IL-1 messenger RNA (mRNA) were detected in 17 of 17 gingival tissue samples from 6 patients. These results demonstrate that IL-1 is produced and released locally in periodontal disease at concentrations sufficient to mediate tissue inflammation and bone resorption. IL-1 may serve as a marker of periodontal tissue destruction.
Periodontitis is a chronic infectious and inflammatory disease which afflicts approximately three quarters of the world’s
adult population over the age of thirty-five. Recently published studies have demonstrated that long-term administration (>-6
months) of non-steroidal anti-inflammatory drugs (NSAIDs) can halt the progressive loss of alveolar bone associated with this
disease. The safe and efficacious twice daily use for six months of 0.1% ketorolac tromethamine oral rinse for the prevention
of periodontal disease progression in adults has recently been demonstrated. This presentation summarizes our results to date
regarding the pharmacokinetics, pharmacodynamics, safety and efficacy of the topical oral rinse form of this potent NSAID
in patients with periodontitis.
A consistent observation in osteoporosis is bone volume reduction accompanied by increased marrow adipose tissue. No single
cause linking the two phenomena has yet been identified. In a human progenitor cell clone (hOP 7) derived from bone marrow,
however, we have demonstrated that rabbit serum can direct differentiation away from an osteoblast lineage to one of adipocytes.
We now report on whether human serum has a similar effect. Serum was collected from 10 pre- and 10 postmenopausal women and
from the 10 postmenopausal women before and following 6-week hormone replacement therapy (HRT). hOP 7 cells were cultured
with the various sera, and after 7-14 days adipocytogenesis was determined by oil red O staining and lipoprotein lipase (LPL)
and glycerol 3-phosphate dehydrogenase (G3PDH) expression. Incubation with 10% premenopausal serum led to labeling of 10.9%
of cells (P<0.05) with oil red O, whereas application of 10% postmenopausal serum led to a much larger effect, 43.5% labeling (P<0.001 with respect to premenopausal serum). Oil red O positivity was accompanied by loss of type I collagen expression
and increased LPL and G3PDH expression. HRT did not reverse the adipocytogenic effect of postmenopausal serum. In conclusion,
serum from postmenopausal women contains factors that steer hOP 7 bone progenitor cells toward an adipocytic phenotype, irrespective
of HRT. The study suggests a role for serum factors in the development of fatty marrow in postmenopausal osteoporosis.
Prostaglandins are inflammatory mediators that are believed to play an important role in the pathophysiology of periodontal
disease. Prostaglandin H synthase (PGHS, EC 1.14.99.1) is the rate-limiting enzyme in prostaglandin biosynthesis. The enzyme
exists as two separately encoded isoforms. PGHS-1 which is constitutively expressed and PGHS-2 which is induced by inflammatory
stimuli. This is the first report describing the expression of the isoenzymes in gingival tissue from patients diagnosed with
adult periodontitis. Tissue was fixed in an alcohol-based fixative and embedded in paraffin. Methods were developed using
immunohistochemical controls, such that embedded sections could be processed and stained using isoform-specific antibodies
and a peroxidase-antiperoxidase immunohistochemistry technique. Along with populations of mononuclear inflammatory cells,
endothelial cells and fibroblasts, the gingival epithelial cell layer appears to be a rich and important source of prostaglandin
production within the periodontium of patients with periodontitis as detected by this newly developed immunohistochemical
staining technique for PGHS-1 and PGHS-2.
With the aim of developing a new periodontal therapeutic modality, guided tissue regeneration (GTR), biodegradable barrier membranes composed of porous poly(l-lactide) (PLLA) films cast on poly(glycolide) (PGA) meshes were fabricated using an in-air drying phase inversion technique. PLLA was dissolved in methylene chloride-ethylacetate mixtures and cast on the knitted PGA meshes, followed by an air-drying process. The use of the three-component polymer solution (PLLA-methylene chloride-ethylacetate) was to generate porous substructures in the PLLA membranes during the solvent evaporation. The PGA meshes mechanically holding the PLLA membranes played an important role in forming the surface pores. Size and morphology of the pores were affected by the solvent composition of methylene chloride and ethylacetate. Regular pores were generated both at the surface and sublayer of the membranes. Flurbiprofen and tetracycline, used in periodontal therapy for their tissue regenerating effects, were incorporated in the membranes by adding the drugs in the PLLA solutions. The drug release kinetics mainly depended upon the hydrophobic-hydrophilic properties of the drugs and the porosity of the membranes regulated by the solvent composition of the PLLA solution. The release rate could be further controlled by loaded drug contents. The drug releasing porous PLLA membranes might be an effective therapeutic system in the treatment of periodontal disease.
Platelet-derived growth factor-BB (PDGF-BB) was incorporated into porous poly (l-lactide) (PLLA) membranes with an aim of improving early bone healing in guided tissue regeneration (GTR) therapy. Porous PDGF-BB loaded membranes were fabricated by coating PDGF-BB-dissolved PLLA methylene chloride–ethyl acetate solutions on polyglycolic acid (PGA) meshes. Release kinetics of PDGF-BB, biologic activity, degradability and guided tissue regenerative potentials of the membranes were investigated. Release of PDGF-BB could be controlled by adding bovine serum albumin that may provide porous diffusion channels for PDGF-BB release and by varying initial loading content of PDGF-BB. Biologic activity of PDGF-BB in the membranes was ascertained by fibroblast chemotaxis. PDGF-BB loaded membranes maintained proper degradation property for periodontal application. PDGF-BB loaded membrane markedly increased new bone formation in rat calvarial defects, and completed bony reunion after 2 weeks of implantation period. These results suggested that PDGF-BB loaded PLLA membrane might potentially enhance guided tissue regenerative efficacy.
With an aim of improving bone regeneration, chitosan sponge containing platelet-derived growth factor-BB (PDGF-BB) were developed. For fabrication of chitosan sponge, chitosan solution was freeze-dried, crosslinked and freeze-dried again. PDGF-BB was incorporated into the chitosan sponge by soaking chitosan sponge into the PDGF-BB solution. Release kinetics of PDGF-BB, cell attachment, proliferation capacity and bony regenerative potentials of PDGF-BB-loaded chitosan sponge were investigated. Prepared chitosan sponge retained porous structure with 100 μm pore diameter that was suitable for cellular migration and growth. Release rate of PDGF-BB could be controlled by varying initial loading content of PDGF-BB to obtain optimal therapeutic efficacy. PDGF-BB-loaded chitosan sponge induced significantly high cell attachment and proliferation level, which indicated good cellular adaptability. PDGF-BB-loaded chitosan sponge demonstrated marked increase in new bone formation and rapid calcification. Degradation of the chitosan sponge was proceeded at defect site and subsequently replaced with new bone. Histomorphometric analysis confirmed that PDGF-BB-loaded chitosan sponge significantly induced new bone formation. These results suggested that chitosan sponge and PDGF-BB-loaded chitosan sponge may be beneficial to enhance periodontal bone regeneration.
Twenty five patients with progresive periodontal disease entered this study in order to examine clinical effects of a non-steroidal anti-inflammatory drug - ibuprofen, used as an adjunct to non-surgical periodontal treatment. After scaling and root planning, patients were randomly assigned to either receive orally 200 mg of ibuprofen per day for one month (group A), or not receive the drug (group B). The obtained results show that the mechanical periodontal treatment brought to resolution the gingival inflammation with both group of patients. Although the mean values of the used indices were lower in group A than in group B, those differences were neither statistically nor clinically significant. We may conclude that systemic ibuprofen had no significant effect on plaque, gingival or bleeding index scores.
It was the aim of the study to evaluate the clinical and antibacterial effect of a dentifrice containing an anti-inflammatory plant extract (SB) versus a placebo (PLA) using an experimental gingivitis model. Forty subjects (20 per group) discontinued all oral hygiene measures for four teeth for a period of 21 days using a shield (to generate a possible gingivitis) while they could brush the other teeth normally. After brushing, the shield was removed and teeth were treated with the randomly assigned toothpaste slurry for 1 min. Löe and Silness gingival index (GI), Silness and Löe plaque index (PI), and biofilm vitality (VF%) were assessed at days 0, 14, and 21, respectively. Subjects of the PLA group developed a GI of 0.82 ± 0.342 (day 14) and 1.585 ± 0.218 (day 21), while the data of the SB group were significantly reduced (0.355 ± 0.243 and 0.934 ± 0.342, p < 0.001). While PI was significantly reduced at all follow-up appointments, reductions in VF reached the level of significance only at day 21. The results suggest that the new toothpaste formulation was able to significantly reduce the extent of gingivitis, plaque development, and vital flora.
To evaluate the effects of adjunctive meloxicam administration on clinical periodontal measurements and gingival crevicular fluid (GCF) prostaglandin E(2) (PGE(2)) and interleukin-1-beta (IL-1beta) levels in chronic periodontitis.
Forty chronic periodontitis patients were randomized to receive either meloxicam 7.5 mg or placebo tablets for 10 days with scaling and root planing (SRP). GCF levels of PGE(2) and IL-1beta at baseline, day 10 of drug intake and 4 weeks after SRP were determined by enzyme-linked immunosorbent assay. Demographic, clinical periodontal data were analyzed using a repeated measures ANOVA and Bonferroni analysis. GCF PGE(2) and IL-1beta levels were compared between different evaluation times using the Friedman test. The Mann-Whitney test was used to compare biochemical data between the study groups. Pearson correlation analysis was used to relate clinical and biochemical data.
Study groups showed significant reductions in all clinical periodontal measurements and GCF volume (p < 0.05). In both groups, IL-1beta was reduced significantly on day 10 and at week 4 compared with baseline (p < 0.01) without significant changes in PGE(2) levels (p > 0.05). No significant differences were found between study groups in GCF IL-1beta or PGE(2) levels (p > 0.05).
Adjunctive meloxicam does not seem to provide additional improvement in clinical parameters or GCF PGE(2) and IL-1beta levels. Larger-scale studies may better clarify potential usage of anti-inflammatory agents in periodontal therapy.
Bisphosphonates are non-metabolized compounds with high affinity for bone mineral hydroxyapatite. These compounds are used in diagnosis and treatment of malignancies metastatic to bone. Currently, IV bisphosphonates are used to treat hypercalcemia of malignancy. There are also "off label" uses to prevent, minimize, or delay skeletal morbidity associated with metastatic bone disease. Osteonecrosis of the jaws is an intraoral complication that has been reported after administration of intravenous nitrogen-containing bisphosphonates. Bisphosphonate associated osteonecrosis (BON) may remain asymptomatic for many weeks or months and is usually recognized clinically by the identification of exposed bone in the oral cavity. Other clinical features of BON are pain, ulceration, necrotic bone and/or local inflammation of the mucosa. Though these are generally all of which are seen later in the disease process. It is theorized that nuclear medicine imaging may play a crucial role in the recognition and identification of these bone lesions earlier in the disease process. Due to the high bone affinity, bisphosphonates coupled to a gamma-emitting radioisotope have been used as bone-scanning agents. Technetium is most commonly used gamma-emitting radioisotope in conjunction with a bisphosphonate. In University of Iowa Hospitals and Clinics, the material of choice is technetium99 methylene diophosphonate (Tc99 MDP). Bisphosphonates have a long half-life in bone and long-term treatment with non-tagged therapeutic bisphosphonates may saturate bone adherence sites and interfering with a single-dose scanning agent used for bone scintigraphy. Alternatively, therapeutic bisphosphonates may alter bone physiology such that scintigraphic findings could be enhanced in some locations and decreased in others. Limitations of the use of scintigraphy in patients on bisphosphonate therapy include low resolution and a difficulty in differentiating between inflammation and metastatic disease especially during the latter stages of the disease. In an effort to understand the effects of this compound on scintigraphic imaging, this study will evaluate any potential changes during and after use of IV bisphosphonates that may confound imaging.
The use of bone-seeking radiopharmaceutical uptake (BSRU) as an indicator of periodontal disease activity was assessed in untreated beagles with naturally occurring periodontal disease, and in beagles treated with the non-steroidal anti-inflammatory drug, flurbiprofen. In untreated beagles, a single uptake measurement was indicative of the rate of bone loss subsequently determined by sequential radiographs. Beagles treated with flurbiprofen demonstrated a significant decrease in rate of bone loss and a corresponding decrease in BSRU. Transfer of this technology to untreated human subjects with moderate to severe periodontal disease also showed a positive correlation between a single measurement of BSRU and the rate of bone loss determined from sequential radiographs. Analysis of these data shows that a single BSRU examination may be indicative of periodontal disease activity.
Digital subtraction radiography requires close matching of the contrast in the films to be subtracted. A digital method is presented permitting the retrospective correction of film contrast differences. The method is nonparametric and derives the required gray level transformation directly from the histograms associated with the radiographs. This transform is shown to be unique and monotonic. It is based on fewer theoretical assumptions than a previously described parametric correction method, and it performs significantly better in reducing the contrast mismatch measured by the standard deviation of the gray levels in the subtraction image.
One of the major successes of nuclear medicine in recent years has been the clinical utility of the 99mTc-labeled bone-imaging agents. This article is concerned with the evidence available for the mechanisms by which these and other such radiopharmaceuticals localize at sites in the skeleton.
1. The placement of cotton floss ligatures in a position apical to the gingival margin of premolars and molars in young dogs induced an acute inflammatory reaction in the periodontal tissues resulting in loss of connective tissue attachment and alveolar bone. 2. Bone resorption could be observed histologically within 7 days, and radiographically within 2 to 3 weeks after ligature placement. 3. Daily administration of indomethacin interfered with the periodontal tissue response to ligature placement. Indomethacin was shown to (i) delay the onset and to suppress the magnitude of the acute inflammatory reaction, and (ii) decrease the degree of alveolar bone resorption.
Previous studies have shown that, following a single injection of 99m-Tc-MDP, measurement of bone-seeking radiopharmaceutical uptake can detect “active” alveolar bone loss due to periodontal disease in beagle dogs, as determined by radiographs taken at the time of, and several months after, the nuclear medicine procedure. The efficacy of this diagnostic test. however, had not been assessed in human periodontal disease. The ability of a single bone-seeking radiopharmaceutical uptake examination to detect “active” alveolar bone loss due to periodontal disease in human patients was assessed by comparing a single uptake measurement to the rate of bone loss determined from serial radiographs taken over a 6-month period. Uptake was expressed as a ratio of the cpm from the alveolar bone divided by the cpm from the non-tooth supporting bone of the nuchal crest. High uptake ratios were associated with “active” loss and low uptake ratios were associated with little if any change in alveolar bone height (p < 0.001). The nuclear medicine examination was an accurate detector of periodontal disease activity in nearly 80% of the individual teeth studied. These data indicate that high bone-seeking radiopharmaceutical uptake ratios may be pathognomonic of active bone loss in human periodontal disease.
The effect of the non-steroidal anti-inflammatory drug flurbiprofen on the progression of periodontal disease was studied in 12 beagle dogs over a 2-yr period. Standardized radiographs were used to measure the rate of bone loss; bone-seeking radiophormaceutical uptake was used to assess the effect on bone metabolism, and gingival inflammation was scored. Following a 6-month pretreatment baseline period. 6 dogs were dosed daily with 0.02 mg/kg flurbiprofen for a 12-month treatment period. Also, one side of the mouth in each dog was treated with periodontal flap surgery at the beginning of the treatment period. After 12 months, flurbiprofen was discontinued and the dogs were studied for a 6-month post-treatment period. In flurbiprofen-treated dogs the rate of bone loss was significantly decreased about both surgically and non-surgically treated teeth throughout the 12-month treatment period. This decreased rate was sustained through 3 months of the post-treatment period, but was lost 6 months following the termination of flurbiprofen therapy. No similar effect on reducing the rate of bone loss was observed in the placebo-treated dogs. A significant decrease in bone-seeking radiopharmaceutical uptake was observed in the flurbiprofen-treated teeth, which corresponded with the radiographic findings. Changes in gingival inflammation with flurbiprofen treatment were not observed. These data indicate that flurbiprofen is a potent inhibitor of alveolar bone loss in beagles and within 6 months of the termination of flurbiprofen the effect on slowing the rate of bone loss is lost.
The use of a cephalostat to stabilize projection geometry for subtraction radiography was investigated. Six replicate repositionings of patients within a cephalostat indicated that the mean angular disparity between repositioning was 0.33 ± 0.10 degrees. Subtraction images produced from films of a phantom with artificial periodontal defects exposed using the cephalostat or stent technique were compared. There was no significant difference in the standard deviations of the gray level histograms obtained using the two methods. However, the ability of 10 investigators to detect the presence or absence of simulated periodontal lesions was superior from subtraction radiographs produced from cephalostat-based images when compared to stent-based images (p < .02). Sets of radiographs taken of 6 patients on the same day or 3 months apart indicate that the cephalometric technique may be used to stabilize projection geometry.
The effect of the nonsteroidal anti-inflammatory drug flurbiprofen has been studied in the ligature-induced and spontaneous periodontitis model in the rhesus monkey, Macaca mulatta. Twenty-four adult monkeys with incipient periodontitis were divided into three disease-matched groups. Two groups received flurbiprofen at dosages of either 0.27 mg/kg/d or 7.1 mg/kg/d delivered systemically via osmotic minipump. A split-mouth approach was used, placing ligatures on one side and monitoring the progression of periodontitis at regular intervals for 6 months. Clinical measurements included standardized radiographs, Ramfjord attachment level determinations and assessments of redness, edema and bleeding on probing. There was a statistically significant inhibition of attachment loss (p < 0.05), gingival redness (p < 0.05) and bleeding on probing (p < 0.05) in ligatureinduced and spontaneous periodontitis in the flurbiprofen-treated animals at 6 months. Eight of 8 ligated control monkeys lost significant attachment (mean loss of 1.06 mm/site). Only 3 of 15 flurbiprofen-treated ligated monkeys lost any significant attachment, with an overall mean loss of 0.34 mm/site, which was significantly less than the control loss of 1.06 mm/site at p = 4.46 times 10-3. The odds of a control ligated monkey undergoing significant attachment loss in 6 months are elevated 29.3-fold, as compared to the flurbiprofen-treated, cohort monkey group. Flurbiprofen treatment also significantly inhibited spontaneous attachment loss for 6 months as compared to control monkeys, at p < 0.05. These data provide further evidence for the central role of cyclooxygenase products in the progression of periodontal disease. The ability of flurbiprofen to inhibit periodontal attachment loss, even in the presence of gross plaque accumulation, has significant implications for the potential use of flurbiprofen as an adjunctive periodontal therapeutic modality.
The effect of two non-steroidal anti-inflammatory drugs, indomethacin and flurbiprofen, on the progression of alveolar bone loss and on the crevicular fluid (CF) levels of four arachidonic acid metabolites was compared in 16 beagle dogs over a 12-month period. Standardized radiographs were used to measure the rate of bone loss. Radioimmunoassay was used to measure CF levels of PGE2, PGF2α, TxB2 and 6K-PGF1α. Following a 6-month pretreatment baseline period, 5 dogs were dosed daily with 1.0 mg/kg indomethacin, 5 dogs were dosed daily with 0.02 mg/kg flurbiprofen, and 6 dogs were dosed with empty gelatin capsules for a 6-month period. With the administration of either indomethacin or flurbiprofen. the CF levels of PGE2, PGF2α, and TxB2 were similarly significantly decreased; 6K-PGF1α levels were not altered. Indomethacin and flurbiprofen did not have a similar effect on reducing the rate of alveolar bone loss. Flurbiprofen significantly decreased rate of bone loss from baseline whereas indomethacin did not. The data indicate that indomethacin and flurbiprofen inhibit CF arachidonic acid metabolite levels in a similar manner, but not rate of bone loss. The data suggest that flurbiprofen's striking effect on inhibiting rate of bone loss cannot be solely attributed to simple cyclooxygenase inhibition with a reduction in CF prostaglandin levels.
The nonsteroidal anti-inflammatory drug, flurbiprofen, a potent cyclooxygenase inhibitor, significantly decreases the resorption
of alveolar bone in naturally occurring chronic destructive periodontal disease in beagles. This observation indicates that
arachidonic acid metabolites are important in the alveolar bone loss of periodontitis and suggests a use for flurbiprofen
in the management of bone resorption disease.
If prostaglandins play a role in bone resorption by dental cysts they must presumably be released at a site accessible to the bone. Bone resorption is not significantly less when the calvaria are incubated with cyst capsule rather than with full thickness cyst wall. The bone resorbing factors therefore seem to be released by the outer capsule adjacent to the bone rather than by the lining epithelium. These observations support the possibility that prostaglandins (perhaps mainly PGE2) produced by dental cyst capsule are responsible for bone resorption by cysts within the jaws.
PGE2 levels in human gingiva from healthy patients and patients with periodontal disease was measured by radioimmunoassay. There was a tenfold elevation of PGE2 levels in diseased as compared with healthy tissue. PGE2 levels of 10−6M or greater were found in purulent exudates from periodontal infections. The results suggest that local PGE2 production may contribute to the inflammatory changes and bone resorption seen in periodontal disease.
A major event in periodontitis is the destruction of alveolar processes. It is demonstrated that indomethacin (IND), an inhibitor of prostaglandin synthesis, can inhibit bone resorption in vitro. The aim of this study was to test the effect of IND on bone destruction in hamster periodontal disease. Its action was compared to calcitonin (CT), an inhibitor of osteoclastic resorption. IND decreased the macroscopic bone loss by 28% and the number of osteoclasts per mm by 55% in diseased animals but not significantly. Conversely CT reduced significantly bone loss (p
A test group of 22 subjects who had been taking non-steroidal anti-inflammatory drugs for periods in excess of one year were matched with a control group of 22 office workers with reference to age and Plaque Index. It was found that the test group had significantly lower values of Gingival Index and shallower depths of pockets than the control group of subjects. There was a trend also for there to be less loss of attachment in the test group. These results were interpreted as indicating that anti-inflammatory drugs may influence the response of the periodontal tissues to plaque by reducing the prostaglandin concentration in the tissues. The slight decrease in loss of attachment in the test group may also be explained by the reduction in prostaglandin synthesis in the subjects taking anti-inflammatory drugs.
Aspirin (ASA) and indomethacin are inhibitors of prostaglandin synthesis and reduce bone resorption in tissue culture stimulated by preparations obtained from human gingival tissue. In a retrospective study, we attempted to determine whether ASA or ASA plus indomethacin exert a bone resorption inhibiting effect on human alveolar bone. Dental radiographs of 75 patients with a history of arthritis and long-term ingestion (greater than 5 years) of ASA were compared with dental radiographs of 75 healthy male volunteers from the VA Dental Longitudinal Study (DLS). Proximal bone loss was measured using a Schei Ruler graded on a 10-point scale. The data indicated that the ASA population presented with significantly fewer sites of 10% or greater mesial and distal bone loss than the healthy control population (P less than 0.05). Mean percentage bone loss for the entire dentition was also lower in the ASA group, although the difference was not statistically significant. As there is no evidence to suggest that inhibition of alveolar bone loss is a natural concomitant of the arthritic process, we conclude that the inhibition of bone loss found in this study was due to the chronic ingestion of ASA or ASA and indomethacin.
Prostaglandin £2 levels and human periodontat disease
- Jm Goodson
- Fe Dewhirst
- Burnetti
Goodson JM. Dewhirst FE, Burnetti A, Prostaglandin £2 levels and human periodontat disease, Prostaglandins 1974; 6: 81-85.
Sup-pression of inflammation and bone
- S Nyman
- He Schroeder
- Lindhe
Nyman S, Schroeder HE. Lindhe J. Sup-pression of inflammation and bone
Wechter HG 6t al. Fliirbiprofen treatment of perio-dontal disease in beagles
- Jeffcoat
- Mk
- Williams
Jeffcoat MK, Williams RC. Wechter HG 6t al. Fliirbiprofen treatment of perio-dontal disease in beagles, J Perio Res 1986; 21: <,24-633,
- Waite I M