No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The effect of ketoprofen cream on periodontal disease in rhesus monkeys
Abstract
Ketoprofen creams were evaluated for the treatment of periodontal disease in a placebo-controlled, double-blind study in the rhesus monkeys, Macaca mulatta. Two formulations containing ketoprofen (1%), with or without vitamin E, were evaluated against appropriate controls (8 monkeys per group). Two weeks prior to treatment, the animals received prophylaxis on only the left side of the mouth (spontaneous model). Selected teeth on the right side of the mouth were ligated (ligature model). The creams were administered to the gingiva once daily at a standard dose of 1.8 ml per monkey for 6 months. Clinical assessments were made 2 wk before initiation, at baseline and 1, 2, 3 and 6 months post-treatment. The clinical parameters included plaque formation, gingival redness, edema, bleeding on probing and Ramfjord Attachment Level measurements (RAL). Radiographs were taken at 2 wk before initiation, baseline and at 3 and 6 months post-treatment. Digital, subtraction radiography was used to measure vertical linear bone loss along the interproximal root surfaces of the left and right mandibular first molars. Gingival crevicular fluid (GCF) was collected for biochemical assays on PGE2, TxB2, LTB4, IL-1 beta and TNF alpha. There were no significant differences among groups with respect to gingival indices. Radiographic data demonstrated significant positive effects on bone activity in both groups treated with ketoprofen formulations with improvement over time in the ligature model (0.01 < or = p < or = 0.04). The placebo group exhibited bone loss of 1.96 +/- 0.48 and 1.40 +/- 0.56 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream showed an apparent bone gain of 0.28 +/- 0.41 and 0.78 +/- 0.47 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream containing vitamin E showed a mean bone loss of 0.41-0.48 mm per site at 3 months with improvement to an apparent bone gain of 0.31 +/- 0.44 mm per site at 6 months. The biochemical data demonstrated early and significant suppression of GCF-LTB4 by both ketoprofen formulations at 1 month, which preceded the significant suppression of GCF-PGE2 at 2 and 3 months in the ligature model (p < 0.003) and at 2 to 6 months in the spontaneous model (p < 0.02). We conclude that ketoprofen at 1% level in suitable topical vehicles can effectively inhibit GCF-LTB4 and GCF-PGE2 and positively alter alveolar bone activity in the ligature-induced model of periodontitis in the monkey.
... Current studies have associated the intake of NSAIDs with bone repair process (2,4,5) and have demonstrated that bone is one of the few tissues with remodeling capacity, being able to recover its structure and function even after a trauma. Direct digital radiography has been largely used in studies investigating bone defects because this methodology is as efficient as conventional radiographic techniques for detection of incipient bone lesions and offers technical resources and tools (softwares) that assist in visualization, delimitation and measurement of these lesions (6,7). ...
... NSAIDs have been shown to effectively inhibit the production of inflammation mediators (prostaglandins and thromboxanes) and are the drugs of choice against inflammatory processes affecting joints, tendons and muscles (1,15). Animal studies have been conducted to investigate the influence of NSAIDs on bone repair process and these drugs have been shown to stimulate bone healing (4)(5)16). However, it has also been reported that NSAIDs may inhibit bone repair depending on the type of drug, period of intake and dosage administered (1,15,17,18). ...
... Li et al. (4) used topical ketoprofen in Rhesus (Macaca mulata) monkeys with periodontal disease at a dose of 1.8 mL/day for 6 months. Radiographs were taken 2 weeks preoperatively, at baseline and 3 and 6 months after surgery. ...
The purpose of this study was to evaluate the influence of ketoprofen on bone repair process in tibiae of rats by means of analysis of the digital optical density. Twenty Wistar rats were assigned to two groups: an untreated control group and a group treated with ketoprofen. The experimental procedures comprised the following stages: general anesthesia, preparation of a unicortical bone defect on the left tibia of each rat, medication with ketoprofen and radiographic examination. Digital radiographic images were acquired using Visualix GX-S-HDI digital sensor and an x-ray equipment. Radiographs were taken at baseline, 7, 14, 21 and 30 days postoperatively and the optical density (OD) was evaluated using the Vix win 1.4 system. The mean values of OD readings were analyzed statistically by ANOVA and Tukey's test with significance level set at á=5%. The control group showed a statistically significant correlation (p=0.001) between time and optical density, while the ketoprofen group exhibited a weak and not statistically significant correlation (p=0.100). The control group presented the smallest OD ratios at days 1 and 7, and the greatest OD ratios at days 14, 21 and 30, with statistically significant difference (p=0.001). There was no significant differences (p=0.100) among the OD ratios in the ketoprofen group, regardless of the evaluation period. The findings of this study suggest that ketoprofen influenced bone repair process because there was an increase in optical density during the first week and delayed new bone formation after the 21st day.
... Entretanto, reconhecida a habilidade em alterar a progressão da doença periodontal por bloquear determinadas respostas do hospedeiro envolvidas no processo destrutivo (WILLIAMS et al., 1989) e com a intenção de minimizar os efeitos colaterais promovidos pelos antiinflamatórios não esteroidais, a utilização de inibidores seletivos de COX-2 ou a utilização de drogas antiinflamatórias aplicadas localmente como em dentifrícios, géis, soluções para bochecho e dispositivos de liberação lenta, poderiam ser efetivos ou apresentar bene-fícios como adjunto à terapia mecânica, na prevenção ou diminuição da perda óssea e perda de inserção decorrente da doença (WILLIAMS et al., 1988;YEWEY et al., 1991;OFFENBACHER et al., 1992;HEASMAN et al., 1993;JEFFCOAT et al., 1995;Li et al., 1996). ...
... Gurgel, em 2003, também demonstrou que após a suspensão da administração do meloxicam, o efeito inibidor do medicamento foi perdido, e que a reabsorção óssea voltou a ocorrer da mesma forma que o grupo não tratado.prostaglandinas, também exercem atividade como potente estimuladora da reabsorção óssea (GOLDHABER et al., 1973) e por encontrarem-se em níveis elevados nos tecidos periodontais e no fluido gengival(OFFENBACHER et al., 1993;Li et al., 1996), é que drogas que inibam a sua produção, por meio do bloqueio da enzima cicloxigenase tem sido discutida na literatura. ...
... These molecules induce further oxidative damage to gingival tissue, periodontal ligaments, and elicit osteoclastic bone resorption [10,131415. The secreted agents also enhance the production of numerous proinflammatory cytokines that contribute to the disease, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNFα), among a broad array of biomolecules that have consistently been reported to be elevated in gingival crevicular fluid (GCF) and tissues of periodontitis patients161718 , rhesus mon- keys [19], and dogs [20]. Levels of these proinflammatory molecules are frequently reduced following periodontal therapy [21, 22]. ...
... to the generation of new knowledge in biological sciences, including periodontology [19, 20,26272829. Periodontal disease can occur naturally or be experimentally induced in animals. ...
Animal models and cell cultures have contributed new knowledge in biological sciences, including periodontology. Although cultured cells can be used to study physiological processes that occur during the pathogenesis of periodontitis, the complex host response fundamentally responsible for this disease cannot be reproduced in vitro. Among the animal kingdom, rodents, rabbits, pigs, dogs, and nonhuman primates have been used to model human periodontitis, each with advantages and disadvantages. Periodontitis commonly has been induced by placing a bacterial plaque retentive ligature in the gingival sulcus around the molar teeth. In addition, alveolar bone loss has been induced by inoculation or injection of human oral bacteria (e.g., Porphyromonas gingivalis) in different animal models. While animal models have provided a wide range of important data, it is sometimes difficult to determine whether the findings are applicable to humans. In addition, variability in host responses to bacterial infection among individuals contributes significantly to the expression of periodontal diseases. A practical and highly reproducible model that truly mimics the natural pathogenesis of human periodontal disease has yet to be developed.
... El flurbiprofeno desaparece a los 7 días del organismo sin efectos secundarios (20). — Li et al (1996) estudiaron el efecto del ketoprofeno tópico en 8 primates (Macaca Rhesus) durante 6 meses. Se trata de un estudio muy completo en el que, por un lado, se hicieron mediciones óseas mediante radiografía digital, encontrando incluso aumento del nivel óseo en comparación con la pérdida observada en el grupo placebo, a los 3 y 6 meses. ...
... — Jeffcoat et al (1995) realizaron mediciones clínicas mediante radiografías, viendo en el grupo del flurbiprofeno una pérdida mayor que en el grupo del ketorolaco, concluyendo que la aplicación de ketorolaco preservaría mas hueso alveolar que el flurbiprofeno sistémico (23). — Li et al (1996) estudiaron el efecto del ketoprofeno y llevaron a cabo mediciones óseas mediante radiografía digital, encontrando incluso aumento del nivel óseo en comparación con la pérdida observada en el grupo placebo, a los 3 y 6 meses (22). — Cavanaugh et al (1998) A la luz de los artículos revisados, parece lógico que el mejor camino por ahora en la inhibición de la cascada inflamatoria que acarrea la destrucción tisular sería la inhibición selectiva de la COX2 mediante fármacos como el celecoxib (no el rofecoxib), con lo que inhibiríamos la creación de PGE 2 y PGF 2 α (y también PAF e IL6 por otras vías poco claras todavía), pero también por inhibición de la 5-LOX, es decir, por la inhibición de la síntesis de leucotrienos, que también se encuentran asociados a la destrucción periodontal. ...
Se presenta una revisión bibliográfica acerca de la aplicación de antiinflamatorios de forma coadyuvante en el tratamiento periodontal. Tras una breve introducción, se establecen las bases inmunológicas de la inflamación y destrucción periodontal, centrándonos en el metabolismo del ácido araquidónico y los cuatro mediadores más implicados actualmente en la destrucción periodontal: prostaglandina E2 (PGE2), prostaglandina F2a (PGF2a), leucotrieno B4 (LTB4) Y factor activador de plaquetas (PAF) , y estableciendo su mecanismo de acción, su relación con la destrucción periodontal a través de las metaloproteinasas (MMPs) y su relación con algunas interleuquinas de la cascada inflamatoria también relacionadas con la destrucción tisular. Después se expone una relación de los fármaco s más empleados en la literatura para la inhibición de todos estos mediadores (Antiinflamatorios no esteroideos o AINEs, ácidos grasos omega3, tetraciclinas y bifosfonatos), explicando su mecanismo de acción y los estudios que los han investigado y posteriormente se ha llevado a cabo una recopilación de los escasos estudios que realizan mediciones clínicas para finalizar estableciendo una serie de conclusiones.
... However, these animal models must be used with utmost care for ethical reasons [3,4]. The animal models have given a lot of knowledge of new concerns in biological sciences [5][6][7][8][9][10].The use of animal models depends on the similarity of it to the human body. The animals chosen for periodontal research are checked for the close relationship to the human anatomy and physiology. ...
Periodontal diseases require treatment at an early stage to prevent further damage and aggravation of the disease. The most commonly seen periodontal diseases are gingivitis and periodontitis. Animals have contributed a major role in studying the different periodontal diseases and providing a proper treatment. Periodontal diseases are either induced in these experimental animal models or can be seen naturally. Different drugs are tested on the animals induced by the disease to find the most effective treatment for that particular disease. Different animals such as mice, rats, pigs, rabbits, hamsters, and rodents are used for the periodontal research. Different animals show a different reaction while some animals show no reaction. Each animal has its own advantages and disadvantages. The use of large animals brings a limitation in the due to its housing difficulties. Animals for periodontal research are chosen depending on their similarity with that of human anatomy and physiology. The use of these animals will help to replicate the disease seen in humans in a better and more accurate way. This will improve the treatment outcome and the prognosis of the disease. The drugs used can, hence, give a better idea about the effect it would have on the human body depending on the effects it shows on the animal models. Hence, the use of appropriate animals for the periodontal research is important to design a better treatment for these diseases. Hence, animal models play an important role in the periodontal research.
... Secondly, thoroughly epithelialized, nonregressive, suprabony pockets with pathologic (rather than surgical) horizontal bone loss can be induced easily (Raymon, 1976). It has been used in various studies like shigella associated periodontitis (Raymon, 1976), other regenerative procedures (Sigurd Ramfjord, 1951), attachment procedures (Raymon, 1976) and to evaluate the bone formation (Li, 1996). ...
this review article emphasis the role of non human primates in periodontal ressearch.
... To the best of our knowledge, this study marks the first time that a pharmacological intervention -whether host-modulation or antimicrobial -is shown to inhibit inflammation in the context of naturally occurring periodontitis in NHPs. Previously conducted studies, including our own, have used inducible models of the disease involving placement of ligatures with or without exogenous inoculation of periodontal pathogens (Page et al., 2007, Assuma et al., 1998, Cappelli et al., 2000, Maekawa et al., 2014a, Moritz et al., 1998, Nisengard et al., 1989, Persson et al., 1994, Li et al., 1996, Offenbacher et al., 1987, Roberts et al., 2004, Pierce and Lindskog, 1987, Shin et al., 2015. The immune system and periodontal anatomy of the cynomolgus monkey is similar to that of humans, and periodontitis in these animals exhibits clinical, microbiological, and immunohistological features that are highly similar to those observed in human periodontitis (Brecx et al., 1985, Page and Schroeder, 1982, Kornman et al., 1981, Ebersole et al., 2014, Ebersole et al., 2002. ...
Aim:
Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. We assessed whether the C3 inhibitor Cp40 inhibits naturally-occurring periodontitis in non-human primates.
Materials and methods:
Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for six weeks followed by a 6-week follow-up period. Clinical periodontal examinations and collection of gingival crevicular fluid and biopsies of gingiva and bone were performed at baseline and during the study. A one-way repeated measures ANOVA was used for data analysis.
Results:
Whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least six weeks following drug discontinuation.
Conclusion:
Cp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in non-human primates, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis. This article is protected by copyright. All rights reserved.
... Both systemic and topical application of non-steroidal anti-inflammatory drugs that inhibit prostaglandin synthesis reduce periodontal bone loss in spontaneously occurring periodontal disease in dogs and in ligature-induced periodontal disease in non-human primates. 44,45 Similarly, application of factors that inhibit cytokines, including tumor necrosis factor [TNF], interleukin [IL]-1, IL-17, complement, and RANKL reduce periodontal tissue destruction whether induced by A. actinomycetemcomitans oral gavage or by ligatures in mice or non-human primates, providing additional evidence that the host response mediates bone loss. 46-55 Moreover, such studies have offered promising therapeutic targets for the treatment of human periodontitis. ...
Abstract Whereas no single animal model can reproduce the complexity of periodontitis, different aspects of the disease can be addressed by distinct models. Despite their limitations, animal models are essential for testing the biological significance of in vitro findings and for establishing cause-and-effect relationships relevant to clinical observations, which are typically correlative. We provide evidence that animal-based studies have provided a durable framework for dissecting the mechanistic basis of periodontitis. These studies have solidified the etiologic role of bacteria in initiating the inflammatory response that leads to periodontal bone loss and have identified key mediators (IL-1, TNF, prostaglandins, complement, RANKL) that induce inflammatory breakdown. Moreover, animal studies suggest that dysbiosis, rather than individual bacterial species, are important in initiating periodontal bone loss and have introduced the concept that organisms previously considered commensals can play important roles as accessory pathogens or pathobionts. These studies have also provided insight as to how systemic conditions, such as diabetes or leukocyte adhesion deficiency, contribute to tissue destruction. In addition, animal studies have identified and been useful in testing therapeutic targets.
... NSAIDs were shown to reduce alveolar bone loss (ABL) associated with periodontal disease (Miyauchi et al., 2004). Various formulations of KP, i.e., 1%w/w cream (Li et al., 1996), 1.5% w/w gel (Lawrence et al., 1998;Srinivas et al., 2011), and KP with fluoride (Bowen et al., 2000) were previously used for the treatment of ligature-induced periodontitis. ...
Aim:
The aim of the novel study was to check the efficacy of a locally applied 2%w/w nanoemulgel (NEG) of Ketoprofen (KP) in preventing the periodontitis, and was also checked NEG without KP to ensure the effect of eugenol in NEG as an oil phase.
Design:
For experimentally induced periodontitis, sterile silk ligatures (3/0) were placed around the crevices of the first left lower molar teeth of the male Wistar rats. During 8 weeks, all rats were fed with 10%w/v sucrose solution. The experimental assessment was carried out at 11 d after treatment of experimental periodontal disease (EPD) rats by various clinical parameters like gingival index (GI), tooth mobility (TM), alveolar bone loss (ABL), histological analysis, detection of TNF-α, and IL-1β in gingival tissue by ELISA and the roughness were measured by atomic force microscopy (AFM) in tapping modes.
Results:
After treatment, comparison studies with EPD were performed. NEG loaded with KP prevents significantly (p < 0.05) various parameters (GI, TM, and ABL), which were responsible for periodontitis. The histopathology of the periodontium showed that Group 3 (NEG loaded with KP) had a more significant reduction in inflammatory cell infiltration, alveolar bones resorption, and cementum (p < 0.05). In the topographical images, significant reduction in roughness of NEG loaded with KP was observed in comparison with EPD without treatment.
Conclusion:
The study revealed the great synergistic potential of the combined NEG of an anti-inflammatory drug KP along with eugenol as the oil phase, which have potential antibacterial, analgesic, and anesthetic properties to combat periodontal disease.
... Gel has been administered into oral surgical sites produced greater analgesic effect. A transdermal KP delivery system on reducing delayed onset muscle soreness have also been studied (53)(54)(55)(56)(57)(58)(59)(60). Also, the effect of different ointment bases on the efficacy of KP topical preparations, dissolution rate of the KP nanoparticle gels forms, transdermal delivery of KP microemulsions and transdermal delivery of the drug from a new soya-lecithin aggregate, have been studied as well (61)(62)(63)(64). ...
Ketoprofen is a 2-(3-benzolphenyl)propionic acid with anti-inflammatory, analgesic and antipyretic properties. It is used in the treatment of variety of acute and chronic inflammatory diseases and including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis as well as menstrual abdominal cramps. Ketoprofen's oral, dermal, rectal or intravenous formulations are available. The average ketoprofen elimination half-life is 2-4 hours. It has a simple metabolism, and a broad therapeutic window, and does not show accumulation in the body following multiple administration. It is metabolized in the liver and excreted in to urine and to a lesser extent in the faeces. In this review, physicochemical, pharmacological and pharmacokinetic properties in addition to bioavailability of ketoprofen are discussed.
... Some positive effects after vitamin E administration on rat bone loss induced by stress have been observed, and vitamin E efficacy was detected only when the stress was introduced abruptly (Cohen . However, other studies found no effects of vitamin E on PD (Li et al., 1996;Cohen etal., 1991). ...
Inrecent years, there hasbeenatremendous expansion inmedical anddental research concerned with free rad- icals, reactive oxygen species, andanti-oxidant defense mechanisms. This review isintended toprovide acritical, up-to-date summary ofthefield, withparticular emphasis onitsimplications fortheapplication of"anti-oxidant therapy" inperiodontal disease. Wehavereviewed thenomenclature, mechanisms ofactions, features, andsources ofmostcommonfree radicals and reactive oxygen species, aswell asanalyzed thetypical biological targets foroxidative damage. Based onareview ofdirect and indirect anti-oxidant hostdefenses, particularly inrelation tothekeyrole ofpolymorphonuclear neutrophils inperiodontitis, wereview current evidence foroxidative damage inchronic inflammatory periodontal disease, andthepossible therapeutic effects ofanti-oxidants intreating and/or preventing suchpathology, withspecial attention tovitamin EandCo-enzyme Q.
... However there is interest in the use of Ketoprofen for the treatment of periodontitis. Ketoprofen is readily absorbed through the cutis, a property observed for other NSAIDs studied by Li et al [10] , and Shah et al [11] . Based on this consideration, there is the potential for topical formulations of Ketoprofen to be absorbed through the oral mucosa, reducing inflammation of the gingival and periodontal tissues. ...
Contribution of engineering to other fields is authentic and increasingly growing. The field of dentistry is an example of fields that are in need for wide and deep cooperation with engineering disciplines. The current work is aimed to investigate the possible change in mechanical properties and surface roughness of a widely used material in dentistry applications, Acrylic resin (Polymethyl methacrylate) after mixing it with Ketoprofen (2% to 10%). This mixing is sought to diminish the possible irritation that could be developed by patients sensitive to Acrylic resin (PMMA) usage. The effect of soaking the material in different solutions having variety of pH values was taken into consideration to simulate the actual service environment. Compressive, bending, and Izod impact tests were carried at room temperature for specimens of PMMA containing different fractions of Ketoprofen (0%, 2%, 5%, and 10%). Surface roughness were measured (Ra) along a period of 5000 hours of soaking in several solutions with different pH values (2, 5, 7, and 11). Only bending strength, among mechanical, was slightly increased with the increased fraction addition of Ketoprofen. Surface roughness was slightly affected with the addition of Ketoprofen. Soaking specimens in different solutions with varying pH showed some tendency to become slightly rougher as the solution has stronger pH value. This effect was more obvious in specimens containing 2% Ketoprofen.
... Williams et al. (1988) using FBP gel that was applied daily into the gingival margins of beagle dogs, reported less bone loss and tooth loss compared to untreated animals. Li et al. (1996) using daily application of ketoprofen gel in rhesus monkeys reported alveolar bone gain compared to placebo control which exhibited net bone loss in an experimental periodontitis and spontaneous periodontitis model. This beneficial effect of the FBP reported in the present study was similar to that found for the CHX chips. ...
The aim of the present randomized, double blind, parallel, 2-arm clinical study was to examine the safety and efficacy of frequent applications of chlorhexidine chip (CHX) and flurbiprofen chip (FBP) in patients with chronic periodontitis.
Sixty patients were randomized into CHX and FBP groups. Following OHI and scaling and root planing (SRP), baseline pocket depth (PD) measurements, gingival recession and bleeding on probing (BOP) were performed and repeated at week 4 and 8. The assigned chip was placed at weeks 0, 1, 2, 3, 5, 7.
Mean PD reduction in the CHX group was 2.08 mm (7.17 to 5.09, p < 0.0001). Mean PD reduction in the FBP group was 2.27 mm (6.72 to 4.45, p < 0.0001). Ninety-seven percentage and 95% of these sites exhibited PD reduction ≥1 mm, while 38% and 34% of the sites exhibited PD ≥3 mm (FBP and CHX, respectively). Clinical attachment level gain (1.66 and 1.95 mm, respectively) was statistically significant (p < 0.0001). Baseline BOP dropped from 98% and 100% to 24% and 30% for the CHX and FBP groups, respectively (p < 0.0001).
Frequent applications of CHX and FBP chips resulted in a significant improvement in the periodontal condition in these sites. Furthermore studies will be required to compare this new treatment regimen to SRP or SRP with single chip application.
... However there is interest in the use of Ketoprofen for the treatment of periodontitis. Ketoprofen is readily absorbed through the cutis, a property observed for other NSAIDs studied by Li et al [10] , and Shah et al [11] . Based on this consideration, there is the potential for topical formulations of Ketoprofen to be absorbed through the oral mucosa, reducing inflammation of the gingival and periodontal tissues. ...
Contribution of engineering to other fields is authentic and increasingly growing. The field of dentistry is an example of fields that are in need for wide and deep cooperation with engineering disciplines. The current work is aimed to investigate the possible change in mechanical properties and surface roughness of a widely used material in dentistry applications, Acrylic resin (Polymethyl methacrylate) after mixing it with Ketoprofen (2% to 10%). This mixing is sought to diminish the possible irritation that could be developed by patients sensitive to Acrylic resin (PMMA) usage. The effect of soaking the material in different solutions having variety of pH values was taken into consideration to simulate the actual service environment. Compressive, bending, and Izod impact tests were carried at room temperature for specimens of PMMA containing different fractions of Ketoprofen (0%, 2%, 5%, and 10%). Surface roughness were measured (Ra) along a period of 5000 hours of soaking in several solutions with different pH values (2, 5, 7, and 11). Only bending strength, among mechanical, was slightly increased with the increased fraction addition of Ketoprofen. Surface roughness was slightly affected with the addition of Ketoprofen. Soaking specimens in different solutions with varying pH showed some tendency to become slightly rougher as the solution has stronger pH value. This effect was more obvious in specimens containing 2% Ketoprofen.
... Since ketoprofen is usually administered to patients over an extended period, several attempts have been made to reduce its adverse side effects. One promising method is to administer the drug through the skin, and various transdermal dosage forms of ketoprofen including patches (Mazieres 2005), gels (Gallagher and Heard 2005;Bowen and Heard 2006), creams (Li et al. 1996), and ointments (Jaeckle, Schaefer, and Loth 2003) have been reported. A variety of physicochemical methods, such as the development of appropriate vehicles (Garcia et al. 2006), iontophoresis (Tashiro et al. 2000), and the use of permeation enhancers (Thomas and Heard 2005) have been developed in an attempt to improve the skin permeation of ketoprofen. ...
Non-invasive transdermal delivery using microneedle arrays was recently introduced to deliver a variety of large and hydrophilic compounds into the skin, including proteins and DNA. In this study, a microneedle array was applied to the delivery of a hydrophobic drug, ketoprofen, to determine if transdermal delivery in rats can be improved without the need for permeation enhancers. The ability of a microneedle to increase the skin permeability of ketoprofen was tested using the following procedure. A microneedle array was inserted into the lower back skin of a rat using a clip for 10 min. Subsequently, 24 mg/kg of a ketoprofen gel was loaded on the same site where the microneedle had been applied. Simultaneously, the microneedle was coated with 24 mg/kg of a ketoprofen gel, and inserted into the skin using a clip for 10 min. As a negative control experiment, only 24 mg/kg of the ketoprofen gel was applied to the shaved lower back of a rat. Blood samples were taken at the indicated times. The plasma concentration (C(p)) was obtained as a function of time (t), and the pharmacokinetic parameters were calculated using the BE program. The group loaded with the microneedle coated with ketoprofen gel showed a 1.86-fold and 2.86-fold increase in the AUC and C((max)) compared with the ketoprofen gel alone group. These results suggest that a microneedle can be an ideal tool for transdermal delivery products.
... Prostaglandin E2 (PGE2), which is present in gingival crevicular fluid (GCF), is associated with alveolar bone resorption, periodontal attachment loss, and inflammation in periodontal tissues (Offenbacher et al., 1984Offenbacher et al., , 1986Offenbacher et al., , 1990Offenbacher et al., , 1991Offenbacher et al., ,1993). An initial six-month pre-clinical pharmacology study demonstrated significant reductions in crevicular fluid prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in monkeys treated for ligature-induced periodontal bone loss with a 1.0% ketoprofen cream formulation (Li et al., 1996). A similar experimental model of alveolar bone loss in beagles showed that dogs treated with 10 mg (S)-ketoprofen capsules or 0.3% or 3.0% (S)-ketoprofen dentifrices had lower rates of bone loss compared with placebo-treated animals over a 60- day dosing period (Paquette et al., 1997b). ...
This clinical trial used a randomized, partially double-blind, controlled parallel design to evaluate the pharmacokinetics and safety of the NSAID, ketoprofen (KTP), in gel formulations. Forty-two subjects, ages 35 to 57 years, with generalized, moderate to advanced adult periodontitis were recruited and randomized to one of 5 treatments over a 14 1/2-day treatment period: (1) 0.5% KTP gel; (2) 1.0% KTP gel; (3) 1.0% KTP alternate gel; (4) 2.0% KTP gel; and (5) 25 mg KTP capsule (positive control). Plasma samples were obtained on days 1 (pre-dosing, 0.5, 1, 2, 3, 6 hr), 8 (pre-dosing, 2 hr), 15 (pre-dosing, 2 hr), and 22 (7 days post-treatment). Plasma KTP concentrations were determined by means of high-performance liquid chromatography. Significant differences in mean area under the plasma concentration vs. time curve (AUC(0-infinity)) among the groups were detected (p < 0.001), with the 25 mg p.o. capsule exhibiting the largest value (5054 ng-hr/mL), the 2.0% gel exhibiting an intermediate value (2244 ng-hr/mL), the 1.0% gels exhibiting lower but comparable values (1516 for the alternate formulation vs. 1461 ng-hr/mL), and the 0.5% gel showing the lowest value (736 ng-hr/mL). Significant differences in dose- and weight-adjusted maximum plasma concentration (Cmax/dose/kg) were detected overall such that the 25 mg p.o. capsule demonstrated higher values as compared with the 4 gel formulations (p = 0.001). The 5 treatments exhibited similar mean times of maximum plasma concentration (tmax) values ranging from 0.6 to 1 hr. Systemic exposures relative to dose and body weight were lower for the gel formulations than for the capsule. The relative systemic bioavailability of the gels compared with peroral administration ranged from 54% to 69%.
... 92 Its administration as a racemic cream (1%), (S)-enantiomer dentifrice (0.3%, 3.0%) or (S)-enantiomer capsule (10.0 mg) was noted to prevent the progression of alveolar bone loss in ligature-induced periodontitis models. 93,94 Ketoprofen appears to be enantioselective with pharmacological benefits restricted to the (S)-enantiomer. 95 The use of enantioselective NSAIDs (e.g., S-ketoprofen) may provide greater efficacy at lower doses and with fewer side effects than other NSAIDs. ...
This paper was prepared by the Research, Science, and Therapy Committee of the American Academy of Periodontology to provide the dental profession an overview of current and potential methods to modulate the host response in the treatment of periodontal diseases. Specifically, it discusses components of periodontal disease pathogenesis (i.e., immune and inflammatory responses, excessive production of matrix metalloproteinases and arachidonic acid metabolites, and regulation of bone metabolism) and their modulation.
... 19,20,32,34 However, as the effect of these drugs on bone only occurs during their administration, 11,17,18 the use of NSAIDs in periodontal therapy greatly depends on patient compliance. Therefore, the use of other manners of administration, such as local delivery, 9,12,15,32,35 should be further investigated to provide a more practical and viable approach for these drugs in periodontal therapy. ...
Anti-inflammatory agents have been reported as a bone loss mediator in periodontitis. This study aimed to investigate in rats the impact of a selective cyclooxygenase-2 inhibitor (meloxicam) on bone loss in ligature-induced periodontitis and its post-treatment effect after administration withdrawal.
Seventy-five adult male Wistar rats were included. After anesthesia, a mandibular first molar was randomly assigned to receive the cotton ligature in the sulcular position, while the contralateral tooth was left unligated. The animals were randomly assigned to one of the following five treatment groups (15 animals each), including daily subcutaneous injections: 1) saline solution for 15 days; 2) saline solution for 45 days; 3) 3 mg/kg of meloxicam for 15 days; 4) 3 mg/kg of meloxicam for 45 days; or 5) 3 mg/kg of meloxicam for 15 days followed by saline solution for 30 days. The animals were sacrificed and the specimens routinely processed. The volume of bone loss was histometrically measured and statistical analysis performed.
Intergroup comparisons demonstrated that the drug may significantly reduce periodontitis-related bone loss (group 3: 5.83 +/- 2.04); however, this effect is less evident when the drug is administered in a short period (group 4: 3.59 +/- 1.57). Moreover, after drug withdrawal, no residual effect was observed (6.86 +/- 3.59, 6.09 +/- 2.66, groups 2 and 5, respectively) (P > 0.05).
Within the limits of the present study, it can be concluded that selective cyclooxygenase-2 inhibitors may reduce bone loss associated with experimental periodontitis and that no remaining effect can be expected after its withdrawal.
... Several topical preparations have been shown to be effective and at the same time avoid the adverse effects of oral delivery of the drug. Ketoprofen cream administered to the gingival for treatment of periodontal disease [3], percutaneous absorption of ketoprofen from creams [4], and the effect of ketoprofen cream on osteopenia [5] have been studied. Also, the effect of different ointment bases on the efficacy of ketoprofen topical preparations [6,7] and transdermal delivery of the drug from a new soya-lecithin aggregate, have been studied [8]. ...
An isocratic RP-HPLC procedure has been developed and validated for the quantitative determination of ketoprofen in a topical gel. The HPLC procedure consist of a YMC ODS-AQ, 5-microm particle size analytical column (150 mm x 4.6 mm); Alltech Econosphere C18, 5-microm particle size guard column; detection at 233 nm; 1 ml/min flow rate; 20-microl injection volume. The mobile phase consisted of pH 3.5 phosphate buffer-water-acetonitrile (8:43:49, v/v). Sample preparation was a simple extraction of ketoprofen with mobile phase. The above conditions resolved and eluted ketoprofen, excipients, and potential degradants within 35 min, with ketoprofen eluting at about 6.5 min. The procedure was validated with respect to specificity, accuracy, precision, and linearity. The accuracy of the procedure, determined by spike recovery measurements, was 100.1-100.5%. The intra- and inter-day precisions were demonstrated by the relative standard deviations (RSD) of 0.3-0.6% and 0.5%, respectively. The intermediate precision was determined by comparing the results obtained with four independently prepared samples by two chemists using two columns on different days. The results indicate no significant difference (P = 0.17). The procedure showed linearity over the concentration range 4 x 10(-5) to 1 x 10(-1) mg/ml.
Background:
Over the past decades, locally delivered host-modulating pharmacological agents have been extensively investigated to treat periodontitis. Although a small category of agents has been tested in clinical trials, most of them were reported in the animal experiments. This systematic review evaluates the efficacy of local application of currently available host-modulating agents, with or without mechanical removal of plaque, in animal models with periodontitis or periodontal defect.
Methods:
PubMed and Embase were searched on February 11, 2019. The inclusion criteria were: 1) experiments were performed in healthy animals (all ages, sexes, and species) with periodontitis, and 2) outcome data for the local application of host-modulating approaches were presented for bone quantity, bone loss and attachment loss and compared to a vehicle control group. Study characteristics and outcome data were extracted and internal validity was assessed. The efficacy of host-modulating agents was analyzed in a meta-analysis. A standardized mean difference and its 95% confidence intervals for each individual comparison were calculated to estimate the overall effect. Subgroup analyses were conducted on animal species and different types of agents.
Results:
Forty-eight papers were included in the review, of which 42 were included in meta-analysis on bone quantity, bone loss and attachment loss. The results showed that host-modulating therapy significantly increased bone formation (SMD: 2.200 [1.560,2.840], n=24), and decreased bone loss (SMD: -1.659 [-1.969, -1.348], n=51) and attachment loss (SMD: -1.572 [-2.211, -0.933], n=17). No significant subgroup effects were identified, indicating that the effects are similar across species and drug types.
Conclusions:
The current scientific evidence supports the use of local host-modulation therapy in the treatment of periodontitis in experimental animals. Our findings appear robust for various animal models and designs included in this review, which increases our confidence of the translational value of the results to the clinical situation.
In their classic 1976 paper, Page & Schroeder described the histopathologic events and the types of myeloid cells and lymphocytes involved in the initiation and progression of inflammatory periodontal disease. The staging of periodontal disease pathogenesis as ‘initial’, ‘early’, ‘established’ and ‘advanced’ lesions productively guided subsequent research in the field and remains fundamentally valid. However, major advances regarding the cellular and molecular mechanisms underlying the induction, regulation and effector functions of immune and inflammatory responses necessitate a reassessment of their work and its integration with emerging new concepts. We now know that each type of leukocyte is actually represented by functionally distinct subsets with different, or even conflicting, roles in immunity and inflammation. Unexpectedly, neutrophils, traditionally regarded as merely antimicrobial effectors in acute conditions and protagonists of the ‘initial’ lesion, are currently appreciated for their functional versatility and critical roles in chronic inflammation. Moreover, an entirely new field of study, osteoimmunology, has emerged and sheds light on the impact of immunoinflammatory events on the skeletal system. These developments and the molecular dissection of crosstalk interactions between innate and adaptive leukocytes, as well as between the immune system and local homeostatic mechanisms, offer a more nuanced understanding of the host response in periodontitis, with profound implications for treatment. At the same time, deeper insights have generated new questions, many of which remain unanswered. In this review, 40 years after Page & Schroeder proposed their model, we summarize enduring and emerging advances in periodontal disease pathogenesis.
The protective effect of Mangifera indica L. extract (Vimang) with antioxidant properties was evaluated based on the existance of evidences of the effectiveness of the antioxidanrt therapies on the periodontal disease. Ten beagle dogs were used. They were induced the periodontal disease by ligature in 3 teeth of the right hemiarch during 21 days. The contralateral teeth were the sound controls. Five dogs selected at random were applied a solution of Vimang in the gingival sulcus twice a day. The rest of the animals received the vehicle in the same way and frequency. The application of the extract significantly reduced the increase of the gingival index, the deepness of the gingival sulcus and the osteal loss. It was concluded that the topical administration of Vimang attenuates the development of the periodontal disease in the ligature-induced model in dogs.
A review about the application of antiinflammatories as an aid for the periodontal treatment is presented. After a brief introduction, we explain the immunological bases of periodontal inflamation and tissue destruction, focusing on arachidonic acid metabolism and the four most important inflammatory mediators now in periodontal tissue resorption: prostaglandin E2 (PGE2), prostaglandin F2a(PGF2a), leucotriene B4 (LTB4) and platelet activation factor (PAF), and explaining their actions and role in inflammation through matrix metalloproteinase (MMPs) and their relation with some other mediators in the inflammatory chain also related with tissue resorption. After, we expound some of the most used drugs for the inhibition of all of these mediators (non-steroid antiinflammatory drugs or NSAIDs, omega3 fatty acids, tetracyclines and bisfosfonates), explaining their action and the papers wich investigated them and later we have made a compilation of the few studies making clinical measurements to finish establishing some conclusions.
Various preclinical/clinical studies support the effectiveness of ketoprofen in periodontitis; however, the literature reveals that novel delivery systems have been less explored for the drug in periodontitis. The current investigation aims to explore the potential of a pro-vesicular approach-based proniosomal drug delivery of ketoprofen for its effectiveness and validation in experimental periodontal disease (EPD). Formulations were developed using I-optimal mixture design. Developed formulations were characterized for entrapment efficiency, vesicle size, and in vitro drug release. Selected proniosomal gels were evaluated for mucoadhesiveness, ex vivo drug permeation, and retention studies. Optimized proniosomal gel was evaluated for surface morphology, rheological behavior, texture studies, and pharmacodynamic activity in EPD. The results showed that ketoprofen-loaded proniosomal formulations formed a mucoadhesive hydrogel comprising spherical and flexible vesicles. Viscosity and texture studies showed good adhesion and smoothness, which are desired for enhanced permeation. The disease condition was improved with preserved bone resorption process, that too with intact cementum vis-à-vis marketed gel formulation, when evaluated in the EPD model. The results lead to the conclusion that proniosomes can act as a promising carrier and can be effectively used for improved ketoprofen delivery in periodontal pockets.
Studies concerning the association between vitamin C and vitamin E levels and periodontal disease are being conducted since many years. In this chapter, the studies published after 1980 are described. A number of studies during this period have demonstrated the association of plasma/serum vitamin C levels with periodontal disease and significant associations between a decreased intake of vitamin C and an increased risk of periodontal disease have been found. Although the efficacy of vitamin C intake on gingival status also has been revealed, its effect on alveolar bone loss is questionable. The number of studies on vitamin E is lower than that on vitamin C; therefore, the effects of vitamin E on periodontal disease are currently unclear. Data collected from the literature suggest that vitamin C may be a potent substance for preventing gingivitis and maintaining healthy periodontal tissues; however, additional research is required to generate conclusive evidence.
Treatment approaches in speech-language therapy are sometimes selected and justified on the basis of a clinician's experience that "it works." Moreover, it has been argued (e.g., Kamhi, 1999) that such clinical judgment is, in principle, sound and should be endorsed. Contrary to this view, five extraneous effects are presented as confounding influences that invalidate clinical judgment as the sole basis for adopting a therapy approach. Clinicians should always question whether observed changes in their patients are due to their interventions or to extraneous effects. Possible controls for these effects are double-blind and single subject repeated measures. Research design suggestions are presented, with descriptions of the five extraneous effects.
Abstract The aim of the present study was to formulate and evaluate in situ gelling syringeable nanoemulgels (NEGs) of ketoprofen for periodontal delivery. Application of 3-factor 3-level design was employed using the Box-Behnken experimental design for the optimization of nanoemulsion using three independent variables such as percent concentration (v/v) of oil (X1), Smix (mixture of surfactant and cosurfactant) (X2) and water (X3); while the particle size (nm) (Y1), polydispersity index (Y2) and zeta potential (mV) (Y3) were used as dependent variables. The NEG was evaluated based on their drug content, pH measurement, mucoadhesion on the goat buccal mucosa, syringeability and inverted sol-gel transition temperature. The drug release data were analyzed for curve fitting based on the Korsmeyer-Peppas law, and the n-values of optimized A5 and A8 formulations were found 0.3721 and 0.3932, respectively, confirmed that both the formulations followed pseudo Fickian diffusion (n < 0.43). The formulation A8 with the optimal drug release was identified as the best NEG formulation. Results of rheological, mucoadhesion and syringeability studies showed the suitability of desired sol-gel property for periodontal drug delivery. The Herschel-Bulkley model was the best fit model to explain the flow behavior of optimized formulation. Using the HET-CAM method, significantly lower in vitro toxicity was indicated the suitability of developed NEG for intra-pocket delivery.
The primary etiology of the periodontal disease is chronic inflammation due to bacterial infection. It is the host's reaction to the presence of bacteria that mediates tissue destruction .Since the destruction of periodontium is believed to be due to the host response , it is intellectual and logical to consider therapeutic approaches that modulate the host response in addition to antibacterial approaches in periodontal therapy. Improved knowledge of bacterium –host interactions and of the process leading to tissue destruction will help to identify targets for host modulation to reduce periodontitis in selected situations .The objective of this article is to review and update the fundamental scientific concepts of host modulation and to furnish an approach to the main types of therapy used, based on the scientific literature.
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.
Lumiracoxib is a selective inhibitor of cyclooxygenase-2 (COX-2) approved for the relief of symptoms of chronic inflammatory conditions. The aim of this study was to evaluate the effects of this specific inhibitor of COX-2 as adjunctive treatment on induced periodontitis in rats. Periodontal disease was induced at the first mandibular molar of 60 rats. After 7 days, the ligature was removed and all animals were submitted to scaling and root planing (SRP) along with local irrigation with saline solution and were divided into 2 groups: SRP (n = 30)-received subcutaneous injections of 1 mg/kg of body weight/day of saline solution for 3 days and; SRP + L (n = 30)-received subcutaneous injections of 1 mg/kg of body weight/day of Lumiracoxib for 3 days. Ten animals in each group were killed at 7, 15, and 30 days. The histological description was performed and the histometric values were statistically analyzed. In Group SRP + L, the histometric analysis (0.58 ± 0.08, 0.64 ± 0.06, and 0.56 ± 0.10 mm(2)) showed less bone loss (p < 0.05) than Group SRP (1.52 ± 0.08, 1.55 ± 0.09, and 1.49 ± 0.24 mm(2)) at 7, 15, and 30 days, respectively. Within the limits of this study it can be concluded that subcutaneous application of specific inhibitor of COX-2 was a beneficial adjunctive treatment for periodontal diseases induced in rats.
Periodontal disease is an inflammatory condition of tooth-supporting tissues. Arachidonic acid metabolites have been implicated in development of periodontal disease, especially those derived from the cyclo-oxygenase (COX) pathway. This study investigated the role of inhibitors of cyclo-oxygenases (COX-1 and COX-2) in a model of periodontal disease in rats.
A ligature was placed around the molar of rats. Losses of fiber attachment and of alveolar bone were measured morphometrically in histologically prepared sections. Infiltration of cells into gingival tissue surrounding the ligated tooth was also determined.
Systemic and local administration of non-selective and selective COX-2 inhibitors, preventively, resulted in significant reduction of the losses of fiber attachment and alveolar bone, as well as decreased leukocyte numbers in gingival tissue. Preventive selective inhibition of COX-1 was as effective as COX-2 inhibition in reducing local fiber attachment loss and cell migration, but did not prevent alveolar bone loss.
Our results provide evidence for participation of COX-1 and COX-2 in early stages of periodontal disease in rats. Furthermore, local administration of COX inhibitors reduced the signs of periodontal disease to the same extent as systemic treatment. Therapeutic approaches incorporating locally delivered anti-inflammatory drugs could be of benefit for patients suffering from periodontal disease.
To evaluate the effects of gel containing Garcinia mangostana L. pericarp extract (GM gel) applied topically as an adjunct to periodontal treatment.
Subjects who had periodontal pockets on their single-rooted teeth were randomized into the test or control group. Subjects in the test group received periodontal treatment consisting of scaling, root planing and subgingival application of GM gel while those in the control group received scaling and root planing without GM gel application.
Mahidol University, Faculty of Dentistry, Thailand.
Clinical parameters included probing pocket depth (PPD), clinical attachment level (CAL), bleeding on probing (BOP), Gingival Index (GI) and Plaque Index (PI). Microbiological parameter included subgingival microbial composition as examined by phase contrast microscopy.
Clinical improvement compared to baseline was found in both groups (P < 0.05). The test group exhibited significantly higher reduction in mean PPD, GI and BOP than the control group at the 3rd month after treatment (P < 0.05). Subgingival microbial composition changed from diseased state to that compatible with health after treatment in both groups. However, significant differences between groups were found only in the mean percentage of cocci at the 1st and 3rd month after treatment (P < 0.05).
GM gel could enhance the clinical effects of periodontal treatment.
The effects of topical ketorolac tromethamine mouthrinse (0.1%) on gingival crevicular fluid (GCF) prostaglandin E2 (PGE2) concentrations were investigated in a 6-week, randomized, double-blind, placebo-controlled, parallel group, single center study of 42 patients with moderately advanced chronic adult periodontitis. Following screening, GCF was sampled from 6 sites per subject with filter paper strips and PGE2 levels measured using an enzyme immunoassay kit. Only those subjects with mouth median GCF PGE2 concentrations >30 ng/ml entered the rinsing phase. Eligible subjects were allocated placebo rinse in the first 2-week period (days 0 through 14), either ketorolac rinse (test group, n = 21) or placebo rinse (control group, n = 21) in the second 2-week period (days 14 through 28), and placebo rinse in the third 2-week period (days 28 through 42). Full mouth median GCF PGE2 concentrations were calculated for each subject at days 0, 14, 28, and 42, and group means were compared. From day 0 to day 14, no significant changes in GCF PGE2 concentrations were detected in either study group (P > 0.05). Utilizing mean GCF PGE2 concentrations at days 0 and 14 as covariates, no significant differences were observed in adjusted mean PGE2 levels at days 28 and 42 between the study groups (ANCOVA, P > 0.05). A statistically significant increase in GCF PGE2 levels was noted at days 28 and 42 in the placebo group (P < 0.01), but not in the ketorolac group (P > 0.05), when compared to baseline, however. GCF PGE2 levels were further studied in a subset of volunteers (n = 11) during a 12-hour period following first rinsing with mouthrinse (active or placebo) at day 14. GCF was sampled 0, 2, 4, 6, 8, and 12 hours post-rinsing. Mean PGE2 levels were higher in the placebo subgroup than in the ketorolac subgroup, and increased gradually over the 12-hour period in both subgroups. These data indicate that 1) 14 days of rinsing with 0.1% ketorolac mouthrinse controlled the elevation of GCF PGE2 observed in the placebo group but did not actually reduce GCF PGE2 concentrations and 2) changes in GCF PGE2 levels were not detectable in the 12-hour period following first rinsing with ketorolac.
The pharmacokinetics of ketoprofen were determined after an intravenous (i.v.) and intramuscular (i.m.) dose of 2.0 mg/kg body weight in five camels (Camelus dromedarius) using gas chromatography/mass spectrometry (GC/MS). The data obtained (median and range) following i.v. administration was as follows: the elimination half-life (t(1/2beta)) was 4.16 (2.65-4.29) h, the steady state volume of distribution (Vss) was 130.2 (103.4-165.3) mL/kg, volume of distribution (area method) (Vd(area)) was 321.5 (211.4-371.0) mL/kg, total body clearance (Cl) was 1.00 (0.88-1.08) mL/min x kg and renal clearance was 0.01 (0.003-0.033) mL/min x kg. Following i.m. administration, the drug was rapidly absorbed with peak serum concentration of 12.2 (4.80-14.4) microg/mL at 1.50 (1.00-2.00) h. The systemic availability of ketoprofen was complete. The apparent half-life was 3.28 (2.56-4.14) h. A hydroxylated metabolite of ketoprofen was identified by (GC/MS) under electron impact (EI) and chemical ionization (CI) scan modes. The detection times for ketoprofen and hydroxy ketoprofen in urine after an intravenous (i.v.) dose of 3.0 mg/kg body weight was 24.00 and 70.00 h, respectively. Serum protein binding of ketoprofen at 20 microg/mL was extensive; (99.1+/-0.15%).
In recent years, there has been a tremendous expansion in medical and dental research concerned with free radicals, reactive oxygen species, and anti-oxidant defense mechanisms. This review is intended to provide a critical, up-to-date summary of the field, with particular emphasis on its implications for the application of "anti-oxidant therapy" in periodontal disease. We have reviewed the nomenclature, mechanisms of actions, features, and sources of most common free radicals and reactive oxygen species, as well as analyzed the typical biological targets for oxidative damage. Based on a review of direct and indirect anti-oxidant host defenses, particularly in relation to the key role of polymorphonuclear neutrophils in periodontitis, we review current evidence for oxidative damage in chronic inflammatory periodontal disease, and the possible therapeutic effects of anti-oxidants in treating and/or preventing such pathology, with special attention to vitamin E and Co-enzyme Q.
Non-steroidal anti-inflammatory agents (e.g., ketoprofen) used topically appear to be effective in reducing bone loss in the ligature model of periodontitis. Ketoprofen, in common with some food preservatives, e.g., benzoate and sorbate, is a weak acid. Fluoride, too, may behave as a weak acid and, similar to the other agents, may exert antibacterial effects. The purpose of the present study was to determine whether a combination of (S)-ketoprofen, an enantiomer of ketoprofen, alone or in combination with fluoride, would suppress Streptococcus sobrinus populations and reduce the incidence of dental caries in rats.
Toothpastes containing ketoprofen and/or monofluorophosphate were applied to the teeth of six groups of 20 rats twice daily for 5 weeks.
Fewest S. sobrinus were found in the group treated with a paste containing 3% (S)-ketoprofen + 0.1% F. This group also displayed the lowest incidence of smooth surface caries of all groups. Severity of sulcal surface caries was also lowest in this group.
Results from this study show that the (S) enantiomer of ketoprofen enhances the caries protective effect of fluoride. It is conceivable that this combination could be effective in combating the two most common maladies of the mouth; periodontal disease and dental caries.
It is just 100 years since the introduction of aspirin to medicine. Since then, aspirin and its derivatives have been joined by acetaminophen, and the nonsteroidal anti-inflammatory drugs--ibuprofen, naproxen sodium, and ketoprofen--as the only over-the-counter (OTC) agents approved by the US Food and Drug Administration for the short-term treatment of pain, headache, dysmenorrhea, and fever. Recently the prescription use of aspirin has expanded to include a number of antiplatelet indications.
The purpose of this paper is to review critically the history, mechanisms of action, efficacy, and tolerability of OTC analgesic and antipyretic products. Relatively new and potential future indications for these drugs are also discussed.
Although all of the OTC analgesic/antipyretic agents seem to share a common mechanism of prostaglandin inhibition, there are important differences in their pharmacology, efficacy, and side-effect profiles. Considering their often-unsupervised use, the risk-benefit ratio of this class of drugs has been extremely favorable. However, when used inappropriately, even these drugs pose significant risks to certain patient populations.
Among the numerous factors of bone remodelling, the local action of arachidonic acid metabolites together with cytokines, is particularly important, especially that of prostaglandin PGE2. It has been suggested that the alveolar bone destruction in periodontal disease and osteoporosis can be treated by reducing the ratio of arachidonic acid in phospholipids, which would diminish prostaglandin production. The aim of this study was to evaluate the main serum polyunsaturated fatty acids and a possible alteration in the level of arachidonic acid in patients suffering from periodontal bone loss. Of the 105 patients who participated the study, 78 were suffering from periodontal bone loss and 27 served as a control group. The fatty acids were measured in serum by gas-chromatography. The results showed that the level of fatty acids of the n-6 pathway was higher in our patients with bone loss than in the control group, whereas the reverse was observed with fatty acids of the n-3 pathway. In conclusion, our patients' bone losses are linked with an imbalance between n-6 and n-3 fatty acids, which seems to justify a diet increase in 20- and 22-carbon fatty acids.
The reported therapeutic benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) in slowing periodontal disease progression appear intimately linked to the effective inhibition of local prostaglandin synthesis. This randomized, partially double-blind, controlled trial was conducted to evaluate the pharmacodynamic effects of the NSAID, ketoprofen (KTP), on gingival crevicular fluid (GCF) prostanoids. 42 subjects, ages 35-57 years, with moderate to advanced adult periodontitis were recruited and monitored for 22 days. On day 1, subjects were randomized for 1 of 5 treatments: i) 0.5% KTP gel; ii) 1.0% KTP gel; iii) 1.0% KTP alternate gel; iv) 2.0% KTP gel; v) 25 mg KTP capsule (positive control). Subjects applied 1 ml of gel topically to their gingiva or administered one capsule p.o., b.i.d. for 14.5 days. GCF samples were collected from posterior, interproximal sites on days 1 (pre-dosing; 1, 2, 3, 6 h), 8 (pre-dosing; 2 h), 15 (pre-dosing; 2 h) and 22 (post-treatment). GCF levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were determined using RIA, and expressed in ng/ml and % reduction from baseline (%Effect). Neither a significant difference among groups nor a dose response in % effect for either prostanoid was evident, both overall and among cohorts with elevated baseline mediator levels ([PGE2]>34 ng/ml; [LTB4]>300 ng/ml). When data were combined from all groups, significant (p<0.01) % reductions in GCF PGE2 were noted at 1 and 2 h post-dosing (29% and 24% respectively). In comparing topical versus systemic formulations, all topical formulations were as equipotent as systemic dosing in altering local prostaglandin levels despite lower KTP exposures with gel treatments. These data indicate that both topical and systemic KTP therapies pharmacodynamically reduce GCF PGE2 levels in adult periodontitis subjects, allowing for potential inhibition of disease progression.
(1) To review computerized a posteriori techniques for geometry and contrast registration prior to digital subtraction in dental radiography; (2) to define a uniform notation for their methodological and technical classification and based on this key code; (3) to derive criteria for successful application of computer-based a posteriori registration for routine clinical subtraction.
All techniques are classified with respect to the (1) dimension of geometry registration; (2) origin; (3) abstraction level, and (4) linkage of features used for registration of geometry; (5) elasticity; (6) domain, and (7) parameter determination of the geometrical transform used; (8) interaction of geometrical registration; as well as (9) origin of features, (10) model of transform, and (11) interaction of procedure for contrast correction.
With respect to clinical practicability, superior registration techniques are based on the low level abstraction of intrinsic features for both geometry and contrast registration. By approximately linking the features, a global projective transform should be generated for geometry registration by automatic methods, while automatic contrast correction should be non-parametric. This challenge is met only by one out of 36 published algorithms. Hence, although numerous computer-based techniques have been published, only a few of them are applied more than once in practice.
The key code proposed in this paper is useful for technical classification of a posteriori registration methods in dental radiography and allows their objective comparison. Further investigations will focus on standardization of practicable procedures to evaluate the robustness of competing methods.
Studies ranging from preclinical animal models to human clinical trials support the basic hypothesis that the inhibition of local arachidonic acid metabolites with nonsteroidal anti-inflammatory drugs slows periodontal disease progression. Data on modulation of other host mediators such as cytokines and NO remain restricted to laboratory or preclinical investigations, but appear promising. It is unlikely that such agents, following regulatory approval, will be used ubiquitously in patient populations, but rather may be targeted for at-risk patients. In the emerging field of periodontal medicine, patient cohorts are currently being identified with genetically based inflammatory mediator hyper-responses (48, 49, 68, 115). Such cohorts who respond to the endotoxin challenge posed by periodontitis with a robust release of cytokines or prostaglandins may benefit most in terms of slowing periodontitis progression and potentially improving systemic susceptibility (3, 67).
To investigate the influence of angular disparity on observer detection of simulated bone gain in digital subtraction radiography using tuned-aperture computed tomography (TACT).
Simulated periodontal defects were created in interproximal and buccal or lingual (tooth-obscured) areas of the premolar and molar regions of a dry human skull. Radiographs were obtained before and after known weights of amorphous bone were added to the defects to simulate bone gain. The skull was positioned in a multidirectional tomographic unit to achieve reproducibility. A series of nine basis images were acquired with a CMOS intra-oral receptor and repeated using angular disparities of 10 degrees, 20 degrees, and 30 degrees. Stacks of TACT slices generated from the basis images were paired for image-registration, histogram-equalization and subtraction using TACT Workbench. Eight calibrated observers randomly assessed the presence or absence of bone gain using a 5-point confidence scale. ROC curves were generated and A(z) values were analysed using ANOVA.
There were significant differences in the performance of the observers (P=0.034), defect location (P=0.005), amount of bone gain (P<0.001), angular disparity (P=0.003) and angular disparity x defect location interaction (P=0.019). Mean A(z) values in detecting bone gain were 0.90, 0.85, 0.79 for angular disparities of 10 degrees, 20 degrees, and 30 degrees respectively.
Smaller angular disparity provided better detection of bone gain with TACT-subtraction using nine basis-projections. This effect of angular disparity was especially evident with tooth-obscured defects.
The purpose of this study was to assess the efficacy of topically applied ketoprofen lysine salt (KLS), a cyclooxygenase inhibitor, against the inflammatory changes induced by interleukin-1beta (IL-1beta) and bradykinin (BK) in hamster cheek pouch microcirculation. In addition, we characterised the pharmacological regulation of IL-1beta activity in this model.
Male Syrian hamsters were used. Microcirculation was visualised by fluorescent microscopy. Leukocyte adhesion, permeability, perfused capillary length (PCL) and capillary red blood cell (RBC) velocity were evaluated.
KLS (25 microg/ml/min to 1.6 mg/ml/min) was topically applied for 3 min before topically administered IL-1beta (1microg/ml) and BK (10(-4) M). Monoclonal anti-mouse IL-1beta receptor antagonist (200 ng/ml), BK-B2 receptor antagonist (10(-6) M), PAF inhibitor (10(-5) M) and cycloheximide (10 microg/ml) were added topically 15, 10, 15 and 60 min, respectively, before IL-1beta (1 microg/ml).
IL-1beta caused a significant increase in microvascular permeability, a decrease in capillary RBC velocity followed by increased leukocyte adhesion in postcapillary venules. BK caused a marked increase in leukocyte adhesion and no decrease in PCL and RBC velocity. Treatment with KLS significantly inhibited both the leukocyte adhesion and microvascular leakage induced by the two mediators. The inflammatory effects induced by IL-1beta were reduced by blockade of IL-1beta receptors and by a BK-B2 receptor antagonist but were not affected by a PAF antagonist and protein synthesis inhibition.
These results demonstrate that KLS is effective in preventing early inflammatory changes induced by both IL-1beta and BK in the capillary network. Prostaglandin release and BK are essential components for IL-beta mediated responses, whereas neither PAF nor new protein synthesis appear to be linked to the early inflammatory changes induced by IL-1beta.
The objective was to review the literature on the effects of selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) on the treatment of periodontal diseases. A search of MEDLINE was conducted and articles published in English until December 2003 were included. The results from in vitro and animal experiments as well as from human clinical trials are presented. Non-selective cyclooxygenase-1 (COX-1) inhibitors used in periodontal research include compounds such as aspirin, flurbiprofen, ibuprofen, naproxen and piroxicam. Selective cyclooxygenase-2 (COX-2) inhibitors represent a new group of pharmaceutical products termed "coxibs" that include meloxicam, nimesulide, etodolac and celecoxib. Evidence from animal experiments and clinical trials documents that selective and non-selective NSAIDs are mainly responsible for the stabilization of periodontal conditions by reducing the rate of alveolar bone resorption. This is achieved through local inhibition of both enzymes (e.g. COX-1 and COX-2) responsible for the synthesis of arachidonic acid metabolites. Evidence shows that the effects of NSAIDs drop off rapidly after drug withdrawal. One of the major advantages of selective COX-2 inhibition is the reduction of adverse systemic effects. Although some studies present promising results, no data from long-term, multicenter prospective clinical trials are yet available for determining whether these therapeutic effects can be retained on a long-term basis. Many of these compounds, such as flurbiprofen, are readily absorbed through the gingival tissues. Therefore, the development of topical NSAIDs formulations (e.g. gels, toothpastes, rinses) with a daily application seems to be of particular interest. This may help to further reduce adverse systemic effects of non-selective NSAIDs in the long-term host modulation of periodontitis-susceptible patients.
To review the biological mechanisms and clinical utility of therapeutic modulation of the host response in the management of periodontal diseases.
A search of MEDLINE-PubMed was performed up to and including December 2004. The search was limited to in vitro, experimental animal and clinical studies published in English. The selection criteria included all levels of available evidence: systematic reviews, randomised-controlled clinical trials, controlled clinical trials, prospective and retrospective cohort studies and case reports of human and experimental animal studies.
Six targets for non-microbial chemotherapeutic intervention were identified. Clinical trials have demonstrated the ability of non-steroidal anti-inflammatory drugs to slow periodontal disease progression. However, recently reported serious adverse effects preclude the use of cyclooxygenase-2 inhibitors as an adjunct to periodontal therapy. Adjunctive use of subantimicrobial dose doxycycline to non-surgical periodontal therapy is beneficial in the management of chronic periodontitis over 12 months. Controversial data exist on the effects of bisphosphonate administration as an adjunct to periodontal therapy. Evidence on modulation of other host mediators including lipoxins, cytokines and nitric oxide synthase is limited to animal research.
After validation in long-term clinical trials, adjunctive host modulation therapy may prove advantageous in the management of periodontal diseases.
Fluid triblock ABA dimethacrylates with A blocks of 2, 4, or 8 lactic acid (LA) and B blocks of 7, 17 or 34 propylene glycol (PG) units were characterized using NMR and crosslinked polymer discs containing 2.5, 5 or 10 wt.% ketoprofen, prednisolone or chlorhexidine diacetate prepared. Disc water sorption, degradation and drug release kinetics were assessed using factorial analysis of gravimetric, acid release and UV spectroscopy studies. With shorter A blocks, conversion of oligomer ends to methacrylate moieties was raised and polymer water sorption reduced. Degradation was generally faster with shorter B and longer A blocks and due to both bulk and surface processes. Raised ketoprofen concentration enhanced polymer degradation. Early ketoprofen release was consistent with Fick's diffusion equation and declined with reduced LA block length. Prednisolone release initially followed Higuchi's equation and declined upon reducing total monomer PG concentration. With slower drug diffusion and higher polymer degradation rate linearity of ketoprofen and prednisolone release improved. Percentage chlorhexidine diacetate release decreased upon reducing A or B block length and drug concentration or particle size. Results were consistent with chlorhexidine diacetate interacting with polymer degradation products thereby slowing release of both.
Ligature-induced periodontitis was monitored for 6 months in eight Macaca mulatta monkeys to examine clinical status, radiographic bone level, and crevicular fluid (CF) levels of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and leukotriene B4 (LTB4). A split-mouth design was used, with eight ligated teeth and eight contralateral nonligated teeth which develop soft-chow-promoted (spontaneous) disease. Ligated sites experienced an average attachment loss of 0.94 mm per site and linear bone loss of 0.88 mm per site, with spontaneous-periodontitis sites experiencing approximately half the loss of ligated sites. The CF mediator levels showed increased levels of PGE2 and TxB2 at the ligated sites, as compared with the spontaneous sites, with no significant contralateral differences in the IL-1 beta or LTB4 responses. The concentrations of LTB4 in CF reached an early threefold peak over the baseline level at 1 month. By 2 months there was a statistically significant threefold elevation in CF-PGE2 in the ligated sites and a twofold elevation in the spontaneous sites as compared to the baseline level (P = 0.041 and 0.008, respectively). The monocyte product IL-1 beta increased sharply at 2 months and returned to the baseline level by 6 months at both ligated and nonligated sites. Tumor necrosis factor alpha in CF was below the limit of detection at all sites throughout the experiment (i.e., < 2 ng/ml). The selective elevation of both PGE2 and TxB2 in ligated sites, compared with levels in spontaneous sites, in the presence of similar levels of LTB4 and IL-1 beta provides further evidence that these molecules regulate the magnitude of the tissue-destructive response in progressive periodontitis.
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.
The effect of the non-steroidal anti-inflammatory drug, naproxen, in reducing periodontal disease activity was assessed in 15 patients with rapidly progressive periodontitis. All patients in this double-blind study were treated with scaling and root planing. Thereafter, 7 patients receiving 500 mg naproxen b.i.d. for 3 months, and 8 patients received placebo. Disease activity was assessed in three ways. First, alveolar bone height was determined using standardized radiography. Second, alterations in alveolar bone metabolism were assessed using 99m-Tc-methylene diphosphonate uptake prior to dosing and 3 months later. Finally, bone loss or gain was detected using digital subtraction radiography. In this study, conventional subtraction images were processed to isolate the area of change and superimpose the change on the original radiograph. This allowed determination of both the direction and location of osseous changes. There was significantly less bone loss as determined by analysis of bone height during the 3-month study in the naproxen-treated patients when compared to the placebo-treated patients (p less than 0.001). Radiopharmaceutical uptake was significantly reduced in the alveolar bone in patients receiving naproxen (p less than 0.03), whereas no significant change was observed in the placebo-treated patients. Furthermore, the subtraction radiographs showed a significant increase in the proportion of teeth demonstrating bone gain in the naproxen-treated group. These findings indicate that naproxen may be a useful adjunct to scaling and root planing in patients with rapidly progressive periodontitis.
The non-steroidal anti-inflammatory drug(NSAID) naproxen was studied in 11 beagle dogs over a 13-month period to determine its effect on the progression of periodontitis. Following a 6-month pretreatment period, 5 dogs received naproxen daily at a dosage of 2.0 mg/kg for 1 month, then 0.2 mg/kg for 6 months. Six control dogs received a gelatin capsule daily as placebo. Standardized radiographs were used to measure the rate of bone loss during the pretreatment and treatment periods. In the control dogs, the rate of bone loss was seen to increase during the treatment period although the increase was not statistically significant. In dogs treated daily with naproxen, the rate of bone loss in the treatment period was significantly less at 4 months of treatment; however, at 7 months the difference, though lower than pretreatment rate, was not significant. When the percent change in rate of bone loss during the overall 7-month treatment period was compared with pretreatment rate, the control dogs demonstrated a 38% increase in rate of bone loss during the treatment period contrasting with a 61% decrease in bone loss rate in naproxen-treated dogs. The data indicate that the non-steroidal anti-inflammatory drug naproxen can significantly inhibit alveolar bone loss in beagles. At 4 months of treatment the rate of bone loss in the naproxen-treated dogs was significantly less than pretreatment, but at 7 months of treatment the rate was no longer statistically significantly less than baseline. This probably reflects a dose response to naproxen treatment for, after 30 days of the treatment period, the naproxen dosage was reduced 10-fold due to tolerance by the beagle.
Ketoprofen has emerged as a potent nonsteroidal anti-inflammatory drug. Its efficacy in the treatment of conditions such as rheumatoid arthritis and osteoarthritis has been demonstrated throughout nearly 20 years of clinical use. It has also been shown to be an effective analgesic. In comparative studies, ketoprofen appears to be at least as effective as other anti-inflammatory and analgesic agents. Because of its short half-life (approximately 1.5 hours) no dosage adjustment appears to be necessary in elderly patients unless there is concomitant renal insufficiency. Although rapidly eliminated from plasma, elimination from synovial fluid is delayed, so therapeutic concentrations can be maintained in affected joints without necessitating frequent administration. The side effects of ketoprofen are similar to those of all NSAIDs, gastrointestinal disturbances being the most frequent. Evidence for the adverse effects of NSAIDs on cartilage is still limited. Drug interactions are similar to those of all NSAIDs, antacids, methotrexate and probenecid being particularly important. Ketoprofen is available in a wide range of formulations, each designed to provide appropriate therapy in specific clinical situations: oral capsules for short term therapy; sustained release forms for chronic therapy and once-daily administration; suppositories to avoid possible gastrointestinal disturbances in susceptible patients; intramuscular preparations for rapid action; and a gel formulation for topical treatment. In the future, research should determine whether ketoprofen and other NSAIDs have any disease-modifying effects on inflammatory conditions in addition to providing symptomatic relief.
Considerable evidence has demonstrated the importance of PGE2 synthesis in the pathogenesis of periodontal disease. Although various cyclooxygenase inhibitors have been known to block periodontal PGE2 synthesis and prevent disease progression in animal models, there are few reports comparing relative efficacies of various inhibitors of arachidonic acid (ARA) metabolism. We have developed a sensitive in vitro assay to measure PGE2 synthesis in periodontal tissues. The apparent IC50 values (i.e. the concentration of drug which causes 50% inhibition of maximum PGE2 synthesis) have been determined for a series of arachidonic acid analogues as well as competitive and non-competitive cyclooxygenase inhibitors. Periodontal tissue homogenates were incubated in the presence of 3H-arachidonic acid for 45 min at 37 degrees C. Inhibitors were tested at 10(-10)-10(-4) M and at zero concentration to measure conversion of 3H-arachidonate to 3H-PGE2. Log or half log dilutions of inhibitors were tested in triplicate for each assay. Radiolabeled PGE2 was extracted from homogenates, purified by reverse phase chromatography and quantitated by double antibody capture. RIA was performed on each homogenate to determine the amount of endogenous unlabeled PGE2 present in the sample to correct for antibody capture recovery. The apparent IC50 values were determined for each drug by averaging two or more replicate assays. Specific total enzymatic activity of periodontal tissue homogenates was typically 5-11 pg PGE2/min/mg tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to alter periodontitis in both animals and humans. This study was initiated in the nonhuman primate (Nhp) model to determine the effect of two NSAIDs on preexisting gingivitis, the conversion of gingivitis to periodontitis, the associated subgingival microbiota, and the gingival PMN response. Eighteen cynomolgus monkeys were divided into three groups and treated on a blind basis with ibuprofen 8%, meclofenamic acid 5%, or placebo applied topically 5 days/week for 20 wk. After 4 wk of treatment, periodontitis was initiated in one quadrant by the placement of silk ligatures. Clinical parameters, bone loss by densitometric analysis of radiographs (CADIA), and cultural microbiology of subgingival plaque were monitored. In situ PMN chemotaxis was assessed by quantitating the PMNs which entered the sulcus in response to a challenge with n-formyl-methionyl-leucyl-phenylalanine (FMLP). No significant differences in the clinical parameters were noted by treatment groups. Radiographic bone loss was detected in all experimental sites in placebo animals as compared with 67% and 44% for ibuprofen and meclofenamic acid animals, respectively. Mean CADIA scores/animal showed a significant loss in bone density for placebo at 6 and 16 wk, no change for ibuprofen animals, and a significant increase in density for meclofenamic acid animals. The microbiota of all groups changed with ligation consistent with previous reports of disease initiation in the Nhp.(ABSTRACT TRUNCATED AT 250 WORDS)
The four principal metabolites of cyclooxygenase (CO) were examined during the progression of experimental periodontitis in the rhesus monkey Macaca mulatta. Thirty-two monkeys were divided in four disease-matched groups. Three groups were treated with flurbiprofen, a potent CO inhibitor, at either 0.027, 0.27 or 7.1 mg/kg/day delivered systemically by a subcutaneously-implanted osmotic mini-pump. We have previously described the findings indicating that flurbiprofen treatment significantly retarded clinical attachment loss (ALOSS), redness and radiographic bone loss (BLOSS). This investigation focuses on the changes in CO metabolites which occur during disease progression of ligature-induced periodontitis and on the dose-response relationship of flurbiprofen, as it relates to disease inhibition and the suppression of ARA metabolites within the crevicular fluid (CF). In untreated animals there was a statistically significant 3-fold increase in CF levels of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) at 3 months, as compared to baseline, which positively correlated with increases in redness, bleeding, ALOSS and BLOSS. CF-PGE2 and TxB2 levels reached a 6-fold peak at 6 months and returned to baseline by 12 months. Flurbiprofen (Fb) prevented the 3-month rise in TxB2, but did not affect the increase in PGE2. At 6 months, Fb administration caused a dose-dependent inhibition of both PGE2 and TxB2. Probit analysis of the dose-response data revealed that the concentration of Fb which caused a 50% inhibition of CF-TxB2 level (the IC50 value for TxB2 synthesis) was approximately two logs lower than the IC50 value for PGE2 synthesis, i.e. TxA2-IC50 = 0.013 vs. PGE2-IC50 = 1.35 mg flurbiprofen/kg/d. The slopes of the PGE2 and TxB2 inhibition curves were identical, consistent with a similar mechanism or singular enzyme for the site of action of Fb inhibition of CO activity. However, the kinetics and sensitivity of Fb inhibition were significantly different for the CO activity responsible for TxB2 and PGE2 synthesis, perhaps due to different compartmentalization of CO within different cell types.
The treatment of human periodontal diseases relies on mechanical and antimicrobial suppression of the etiologic bacteria. The ability to alter the progression of periodontitis by additionally blocking host pathways involved in the destructive process is an area of current research. Prostaglandins and other metabolites of arachidonic acid are believed to be important host mediators of the bone resorption of diseases such as periodontitis. We have previously examined the effect of inhibitors of prostaglandin production, non-steroidal anti-inflammatory drugs (NSAIDs), on inhibiting alveolar bone loss in beagles. The present study was designed to examine the effect of the NSAID, flurbiprofen, on slowing the radiographic loss of alveolar bone in the human. Fifty-six individuals with radiographic evidence of alveolar bone loss were recruited for study. Forty-four patients remained in the study for the data analysis of loss of alveolar bone. Following a 6 month baseline pretreatment period to measure the radiographic progression of bone loss, half of the patients were administered flurbiprofen, 50 mg. b.i.d., while half were administered a placebo. All patients received a subgingival scaling and pumice by a hygienist every 6 months. The rate of alveolar bone loss in a 2 year treatment period was compared to the baseline 6 month pretreatment period within and between patient groups. Throughout the study, teeth exhibiting obvious loss of bone were exited from study and treated with conventional mechanical therapy. At the end of the pretreatment period both patient groups had a similar mean rate of alveolar bone loss.(ABSTRACT TRUNCATED AT 250 WORDS)
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 effect of two non-steroidal anti-inflammatory drugs, indomethacin and flurbiprofen, on the progression of periodontal disease was studied in 16 beagle dogs over a 12-month period. Standardized radiographs were used to measure the rate of bone loss. 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. In the untreated control dogs, the rate of bone loss in the treatment period significantly increased from baseline. In contrast, the rate of bone loss significantly decreased from baseline in the flurbiprofen-treated dogs. In the indomethacin-treated dogs, rate of bone loss in the treatment period was not significantly different from baseline. The data indicate that both flurbiprofen and indomethacin inhibit alveolar bone loss in beagles compared to untreated controls. The data also indicate that with the dosages employed flurbiprofen is overall more effective.
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 effect of the non-steroidal anti-inflammatory drug flurbiprofen, topically applied, on the progression of periodontal disease was studied in 12 beagle dogs over a 13-month period. Standardized radiographs were used to measure the rate of bone loss. Following a 6-month pretreatment baseline period, 6 dogs were treated daily with 0.3 mg flurbiprofen gently applied to the gingival margin in 1 ml of gel vehicle. Six untreated dogs served as controls. In the untreated control dogs the rate of bone loss in the treatment period did not change significantly from baseline, although the rate was elevated by 38%. In contrast, the rate of bone loss significantly decreased by 71% from baseline in the flurbiprofen-treated dogs. The untreated control dogs lost 10 teeth during the treatment period whereas the topical flurbiprofen-treated dogs lost only 1 tooth. The data indicate that topical application of flurbiprofen in a gel vehicle significantly inhibits alveolar bone loss in beagles over a 7-month treatment period. The data also indicate that topical flurbiprofen is associated with the loss of considerably less teeth than in untreated control dogs over the 7-month treatment period.
The effect of the non-steroidal anti-inflammatory drug, ibuprofen, on the progression of periodontal disease was studied in 22 beagle dogs over a 13-month period. Standardized radiographs were used to measure the rate of bone loss. Following a 6-month pretreatment baseline period. 6 dogs were treated daily with 4 mg/kg ibuprofen, 5 dogs were treated with 4 mg/kg ibuprofen in a sustained release preparation, 5 dogs were treated with 0.4 mg/kg ibuprofen and 6 untreated dogs served as controls. In the untreated control dogs the rate of bone loss in the treatment period did not change significantly from baseline, although the rate was increased. In both the 4.0 mg/kg and sustained release 4.0 mg/kg ibuprofen-treated dogs the rate of bone loss in the treatment period was significantly less than the pretreatment period rate. In the 0.4 mg/kg ibuprofen-treated dogs the rate of bone loss, although reduced, was not significantly less than the pretreatment rate. When the rate of bone loss in the control dogs was compared with the rate of bone loss in the ibuprofen-treated dogs, all three ibuprofen-treated groups of dogs had significantly less bone loss than the control dogs. The untreated control dogs lost 10 teeth during the treatment period, whereas the 4.0 mg/kg and 0.4 mg/kg ibuprofen-treated dogs lost 6 teeth and the sustained release 4.0 mg/kg ibuprofen-treated dogs lost 2 teeth during the treatment period. The data indicate that a propionic acid derivative, the non-steroidal anti-inflammatory drug, ibuprofen, can significantly inhibit alveolar bone loss in beagles. Sustained release ibuprofen. which gave consistently greater blood levels over 24 h, was overall more effective.
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
The skin permeabilities of a series of eight salicylates and ten non-steroidal anti-inflammatory drugs were investigated in human subjects. The logarithms of % absorption through intact skin and of n-octanol/water partition coefficients (log P) of the test compounds were plotted against one another, and a parabolic relationship was obtained in both compound series.
Nuclear medicine was used to assess the activity of alveolar bone loss in beagle dogs treated with the nonsteroidal anti-inflammatory drug flurbiprofen. Radiographic measurements of the rate of bone loss were taken during a 6-month "pretreatment" period and a 9-month treatment period. During the treatment period six dogs received a placebo, and six dogs received orally 0.02 mg/kg flurbiprofen daily for 9 months. In addition, each dog received periodontal surgery in one half of the mouth at the end of the pretreatment period. The rate of alveolar bone loss was significantly decreased in the treatment period in the flurbiprofen-treated dogs (P less than 0.001). Measurements of bone-seeking radiopharmaceutical uptake were taken 3 months after the initiation of therapy. The single measurement of uptake was compared to the rate of bone loss determined from repeated radiographs taken during the 9-month treatment period. Bone-seeking radiopharmaceutical uptake was an accurate indicator of "active" bone loss in 83.5% of the teeth studied.
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.
This study was undertaken to determine if prostaglandins play a role in the events leading to loss of bone in the ligature model of periodontitis. Periodontitis was induced by placement of the ligatures around mandibular teeth on one side of the jaw of squirrel monkeys (Saimiri sciureus). From one day prior to ligature placement, half the animals were administered indomethacin (5 mg/kg/day), a potent inhibitor of prostaglandin synthesis. Animals were sacrificed after one and two weeks of experimental periodontitis. It was found that indomethacin treatment abolished the significant losses of alveolar bone height and bone mass seen in non-indomethacin-treated (NIT) animals following ligature placement. Indomethacin also depressed the large increase in osteoclast density measured at one week in the NIT animals. The results support the hypothesis that prostaglandins are an important mediator of bone loss in the ligature model of periodontitis. Evidence is also presented for the coupling of bone resorption with osteoblastic neo-osteogenesis on both periodontal ligament and endosteal bone surfaces.
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
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.
Systemic non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce alveolar bone loss in periodontitis. This study assesses the efficacy of a topical NSAID rinse, containing ketorolac tromethamine as the active agent. Adult periodontitis patients (n = 55) were studied in this 6-month randomized, double blind, parallel, placebo and positive-controlled study. Each patient had a least 3 sites at high risk for bone loss as assessed by low dose bone scan. Groups, balanced for gender, were assigned to one of three regimens: bid ketorolac rinse (0.1%) with placebo capsule; 50 mg bid flurbiprofen capsule (positive control) with placebo rinse; or bid placebo rinse and capsule. Prophylaxes were provided every 3 months. Monthly examinations assessed safety, gingival condition, and gingival crevicular fluid PGE2. Standardized radiographs were taken at baseline and at 3 and 6 months for digital subtraction radiography. A significant loss in bone height was observed during the study period in the placebo group (-0.63 +/- 0.11; P < 0.001), but not in the flurbiprofen (-0.10 +/- 0.12; P = 0.40) or ketorolac rinse (+0.20 +/- 0.11 mm; P = 0.07) groups. Nested ANOVA revealed that ketorolac and flurbiprofen groups had less bone loss (P < 0.01) and reduced gingival crevicular fluid PGE2 levels (P < 0.03) compared to placebo. ANOVA suggests (P = 0.06) that ketorolac rinse preserved more alveolar bone than systemic flurbiprofen at the dose regimens utilized. These data indicate that ketorolac rinse may be beneficial in the treatment of adult periodontitis.
A clinical trial was undertaken to examine the effects of a potent cyclooxygenase inhibitor, flurbiprofen, on both developing and established gingivitis in humans. 21 subjects with healthy gingiva abstained from all oral hygiene procedures for 21 days. 7 subjects were prescribed flurbiprofen, 50 mg b.d. beginning from baseline and a control group (Cl, n = 14) were given placebo. Gingival redness and bleeding on probing were assessed at baseline, 7, 14 and 21 days. Crevicular fluid (GCF) samples were also taken to determine concentrations of PGE2, TxB2 and LTB4 at baseline and at 21 days. Results show that flurbiprofen significantly inhibited the development of redness and bleeding (p < 0.001) effects which were associated with a significant inhibition of TxB2 (p < 0.05). There were no apparent flurbiprofen effects on GCF-PGE2 or GCF-LTB4 during this 21-day gingivitis, model To assess the effects of flurbiprofen on established experimental gingivitis, the model was extended to 28 days. On day 21, the Cl group was subdivided into 2 groups of 7 subjects. One group was prescribed flurbiprofen (50 mg b.d.) for 7 days and controls (C2) continued to take placebo. All subjects continued to abstain from tooth cleaning. Pretreatment (day 21) and post-treatment (day 28) comparisons showed that flurbiprofen again significantly inhibited bleeding (p < 0.001), but did not affect redness. Control subjects demonstrated a significant elevation in gingival bleeding on day 28, and this was associated with significant rises in GCF-PGE2 (p < 0.001), GCF-TxB2 (p < 0.01) and GCF-LTB4 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Topical flurbiprofen in the management of chronic periodontal disease
- Heasman PA
Efficacy of Meclomen as an adjunct in periodontitis therapy
- Reddy MS