RESUMEN
OAS-1000 is a semisynthetic derivative of pseudopterosine A, isolated from sea whip (Pseudopterogorgia elizabethae), that has been shown to have topical anti-inflammatory activity. The purpose of this research was to investigate OAS-1000 for potential use as an anti-inflammatory agent for topical oral application, and to begin to investigate a mechanism of action. OAS-1000 was therefore evaluated as an inhibitor of 4 enzymes of the arachidonic acid metabolic pathways (prostaglandin G/H synthase I (PGHS-1, COX-1), prostaglandin G/H synthase II (PGHS-2, COX-2), arachidonate 5-lipoxygenase (5-LOX), and arachidonate 15-lipoxygenase (15-LOX)). It was found that OAS-1000 inhibits PGHS-1 activity with an IC-50 value of 80.3 microM, but had much less activity versus PGHS-2 enzyme and no activity versus the 15-LOX enzyme. 5-LOX activity showed some inhibition, but only at a high OAS-1000 concentrations. Additionally, OAS-1000 was tested for it's ability inhibit 1 ng/ml IL-1beta stimulated PGE2 production in a cell culture system. Inhibition of 46% was seen at an OAS-1000 concentration of 22.4 microM. Taken together, these experiments suggest that at least some of the topical anti-inflammatory activity of OAS-1000 may be attributed to inhibition of the arachidonic acid metabolites that have been shown to be important in inflammation and tissue destruction.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Diterpenos/farmacología , Glicósidos/farmacología , Mediadores de Inflamación/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Células Cultivadas , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/antagonistas & inhibidores , Diterpenos/administración & dosificación , Relación Dosis-Respuesta a Droga , Glicósidos/administración & dosificación , Humanos , Interleucina-1/farmacología , Inhibidores de la Lipooxigenasa , Mesodermo/citología , Mesodermo/efectos de los fármacos , Mesodermo/enzimología , Análisis de RegresiónRESUMEN
This presentation provides an overview of the technologies available for the chemical control of plaque. It is generally accepted that the formation of dental plaque at the interfaces of tooth/gingiva is one of the major causes of gingival inflammation and dental caries. Several therapeutic approaches have been used to control dental plaque and supragingival infections. These include fluoride preparations such as stannous fluoride, oxygenating agents, anti-attachment agents, and cationic and non-cationic antibacterial agents. Among the fluoride preparations, stable stannous fluoride pastes and gels have been shown to reduce supragingival plaque, gingivitis, hypersensitivity and caries. The effect of the oxygenating agents on the supragingival plaque has been equivocal, but recent data indicate that a stable agent which provides sustained active oxygen release is effective in controlling plaque. A polymer, PVPA, which reduced attachment of bacteria to teeth was shown to significantly reduce plaque formation in humans. A new generation of antibacterials includes non-ionics such as triclosan, which in combination with a special polymer delivery system, has been shown to reduce plaque, gingivitis, supragingival calculus and dental caries in long-term studies conducted around the world. Unlike the first generation of agents, the triclosan/copolymer/sodium fluoride system is effective in long-term clinicals and does not cause staining of teeth, increase in calculus, or disturbance in the oral microbial ecology.
Asunto(s)
Antiinfecciosos Locales/uso terapéutico , Bacterias/efectos de los fármacos , Placa Dental/prevención & control , Adhesión Bacteriana/efectos de los fármacos , Cariostáticos/administración & dosificación , Cariostáticos/uso terapéutico , Cationes , Quimioprevención , Cálculos Dentales/prevención & control , Caries Dental/etiología , Caries Dental/prevención & control , Placa Dental/microbiología , Sensibilidad de la Dentina/prevención & control , Geles , Encía/microbiología , Gingivitis/etiología , Gingivitis/prevención & control , Humanos , Estudios Longitudinales , Organofosfonatos/uso terapéutico , Oxidantes/uso terapéutico , Polivinilos/uso terapéutico , Fluoruro de Sodio/uso terapéutico , Fluoruros de Estaño/administración & dosificación , Fluoruros de Estaño/uso terapéutico , Diente/microbiología , Decoloración de Dientes/prevención & control , Pastas de Dientes , Triclosán/uso terapéuticoRESUMEN
Salifluor (5-n-octanoyl-3'-trifluoromethyl-salicylanilide), a broad spectrum antimicrobial agent, was investigated for its ability to inhibit dental plaque formation. A combination of salifluor with PVM/MA copolymer and NaF was optimized for its antiplaque effect in mouthrinse and dentifrice formulations based on a series of both laboratory and clinical studies. It was found that salifluor, a highly hydrophobic compound, could not be adequately solubilized with the conventional amount of sodium lauryl sulfate (SLS), the most commonly used anionic surfactant in oral hygiene products. However, it was possible to prepare stable mouthrinse formulations using a mixed surfactant system containing both anionic and nonionic surfactants. The most suitable mixture was found to be a combination of SLS, Pluronic and Tauranol in a proportion of 1:1:1. This combination provided adequate stability and high antimicrobial activity as determined by in vitro microbiological tests. Addition of a PVM/MA copolymer to the formulation improved the adsorption and retention of salifluor on stimulated tooth surfaces in vitro (saliva coated hydroxyapatite disks) by almost two-fold and also increased the antiplaque efficacy in both laboratory and human clinical studies. It was also found that a non fluoride dentifrice containing a combination of salifluor and PVM/MA copolymer with a dicalcium phosphate dihydrate abrasive, was highly effective in reducing smooth surface and fissure caries in rats. The results of the present studies demonstrated that salifluor is an effective antiplaque agent in mouthrinse and dentifrice when carefully formulated to maximize its delivery and bioavailability on oral surfaces. They also illustrated the difficulties encountered in exploiting the antimicrobial efficacy of highly hydrophobic, nonionic antimicrobial agents such as salifluor in commonly used oral hygiene vehicles.
Asunto(s)
Antiinfecciosos Locales/uso terapéutico , Placa Dental/prevención & control , Salicilanilidas/uso terapéutico , Adsorción , Aggregatibacter actinomycetemcomitans/efectos de los fármacos , Animales , Antiinfecciosos Locales/farmacología , Cariostáticos/uso terapéutico , Dentífricos/farmacología , Dentífricos/uso terapéutico , Difosfatos/uso terapéutico , Combinación de Medicamentos , Durapatita , Humanos , Maleatos/uso terapéutico , Micelas , Pruebas de Sensibilidad Microbiana , Antisépticos Bucales/farmacología , Antisépticos Bucales/uso terapéutico , Polietilenos/uso terapéutico , Ratas , Salicilanilidas/farmacología , Fluoruro de Sodio/uso terapéutico , Streptococcus mutans/efectos de los fármacos , TensoactivosRESUMEN
Triclosan (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. Triclosan inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. Triclosan also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM. Hence, triclosan has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that triclosan inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antiinfecciosos Locales/farmacología , Antiinflamatorios no Esteroideos/farmacología , Gingivitis/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Triclosán/farmacología , Antiinfecciosos Locales/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Células Cultivadas , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/antagonistas & inhibidores , Dinoprostona/metabolismo , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Encía/citología , Encía/efectos de los fármacos , Encía/enzimología , Gingivitis/enzimología , Humanos , Interleucina-1/farmacología , Inhibidores de la Lipooxigenasa/administración & dosificación , Inhibidores de la Lipooxigenasa/farmacología , Triclosán/administración & dosificaciónRESUMEN
We developed an experimental in vitro model of dental plaque to assess the potential efficacy of antiplaque agents. The model used a chemostat, which provided a continuous source of 5 species of oral bacteria grown in an artificial "saliva-like" medium. This mixture was pumped through six flow cells, each containing two types of surfaces on which plaque formed and was subsequently measured. Formation of bacterial plaque on hydroxyapatite surfaces was assessed by measurement of the DNA and protein content of the plaque film. The amount of bacterial plaque formed on germanium surfaces was measured by attenuated total reflectance (ATR/FT-IR) spectroscopy. Plaque viability was also assessed by a fluorescent staining technique. The quantity of plaque formed on both types of surfaces gradually increased with the duration of flow (from 24 to 72 h) through the cells during a 72-hour experimental period. The flow cells were then pulsed with experimental treatment solutions for 30 s, twice daily. Parallel to results of human clinical studies, the model was capable of discriminating among water, a placebo mouthrinse, and an active antimicrobial mouthrinse formulation containing 0.03% triclosan. It therefore offers a valuable alternative to animal model testing and allows for more rapid evaluations under well-controlled experimental conditions.
Asunto(s)
Técnicas Bacteriológicas/instrumentación , Placa Dental/microbiología , Evaluación Preclínica de Medicamentos/métodos , Antisépticos Bucales/farmacología , Actinomyces viscosus/efectos de los fármacos , Actinomyces viscosus/crecimiento & desarrollo , Alternativas a las Pruebas en Animales , Placa Dental/prevención & control , Cámaras de Difusión de Cultivos , Durapatita , Citometría de Flujo/métodos , Fusobacterium nucleatum/efectos de los fármacos , Fusobacterium nucleatum/crecimiento & desarrollo , Germanio , Pruebas de Sensibilidad Microbiana/métodos , Modelos Biológicos , Reproducibilidad de los Resultados , Saliva/metabolismo , Saliva/microbiología , Espectroscopía Infrarroja por Transformada de Fourier , Streptococcus/efectos de los fármacos , Streptococcus/crecimiento & desarrollo , Triclosán/farmacología , Veillonella/efectos de los fármacos , Veillonella/crecimiento & desarrolloRESUMEN
A dentifrice containing triclosan/PVM/MA, copolymer/NaF (Total) combination was compared with dentifrices containing triclosan without the copolymer system. A variety of laboratory, animal and human studies indicated that Total provided higher uptake and retention of triclosan on teeth, and was more effective in reducing plaque in chemostat and flow cell models. The retention of triclosan in dental plaque was significantly higher with Total as compared with other dentifrices 2 hours post brushing. The triclosan retained in the plaque after using Total was effective against plaque bacteria for up to 12 hours. Other dentifrices did not provide a sustained antibacterial effect against plaque. The results indicated that the delivery system with the copolymer significantly enhanced the efficacy of triclosan against plaque, gingivitis and plaque related diseases in vivo.
Asunto(s)
Cálculos Dentales/prevención & control , Caries Dental/prevención & control , Placa Dental/prevención & control , Dentífricos , Gingivitis/prevención & control , Maleatos , Polietilenos , Fluoruro de Sodio/uso terapéutico , Triclosán/uso terapéutico , Adsorción , Animales , Placa Dental/fisiopatología , Dentífricos/química , Método Doble Ciego , Sistemas de Liberación de Medicamentos , Durapatita/química , Humanos , Técnicas In Vitro , Maleatos/química , Ciencia del Laboratorio Clínico , Polietilenos/química , Ratas , Ratas Endogámicas , Saliva/química , Fluoruro de Sodio/administración & dosificación , Fluoruro de Sodio/química , Cepillado Dental , Triclosán/administración & dosificación , Triclosán/químicaRESUMEN
Mouthrinses are a convenient and accepted method of delivering oral therapeutic agents. Efficacy, however, depends on several factors including the type of drug used and its properties, use of an optimal delivery vehicle, patient compliance or usage practices and the therapeutic indication for which they are used. Three classes of therapeutic agents currently used in mouthrinses are reviewed, including fluorides, tartar control agents and antimicrobial compounds. The specific agents in these categories, some of which are currently used in mouthrinses, span a broad range of chemical and pharmacological properties. A basic understanding of these properties allows for a rational use of these agents in therapeutically optimised formulations.
Asunto(s)
Antisépticos Bucales/uso terapéutico , Antiinfecciosos/administración & dosificación , Antiinfecciosos/uso terapéutico , Difosfatos/administración & dosificación , Difosfatos/uso terapéutico , Fluoruros/administración & dosificación , Fluoruros/uso terapéutico , HumanosRESUMEN
Studies were conducted to determine fluoride availability in saliva after dentifrice use and to relate this parameter to cariostatic efficacy in rat caries experiments. Three dentifrices--two commercial formulations (Colgate Winterfresh Gel and Crest Dentifrice with Na-Sr-polyacrylate) and an Experimental dentifrice--were compared with respect to salivary fluoride availability. All of the dentifrices tested contained 1100 ppm F as sodium fluoride. It was observed that the Experimental dentifrice and Crest dentifrice with Sr-polyacrylate exhibited low salivary fluoride availability relative to the Colgate Winterfresh Gel. Salivary fluoride availability was assessed by means of two parameters: (a) the fluoride concentration in the dentifrice saliva slurry expectorated after brushing, and (b) the area under the curve of salivary F concentration vs. time for up to two hours after dentifrice use. In two rat caries experiments, it was observed that both the Experimental dentifrice and the Sr-polyacrylate dentifrice provided less cariostatic efficacy than the clinically validated Positive Control (Colgate Winterfesh Gel). Analysis of these data provides further evidence in support of the concept that fluoride availability in saliva following dentifrice use is an important parameter related to anticaries efficacy.
Asunto(s)
Caries Dental/prevención & control , Dentífricos/uso terapéutico , Fluoruros/farmacocinética , Saliva/metabolismo , Fluoruro de Sodio/uso terapéutico , Resinas Acrílicas/uso terapéutico , Adulto , Animales , Disponibilidad Biológica , Cariostáticos/uso terapéutico , Dentífricos/química , Método Doble Ciego , Femenino , Fluoruros/análisis , Humanos , Masculino , Placebos , Ratas , Ratas Endogámicas , Saliva/química , Fluoruro de Sodio/administración & dosificación , Estroncio/uso terapéutico , Factores de TiempoRESUMEN
The inhibitory effect of PVM/MA copolymer on the alkaline phosphatase (AP) of E. coli was investigated. Kinetic studies indicated that enzyme inhibition was characterized by a reduction in both the Vmax and the Km. Addition of 1 mM zinc or magnesium ions to the reaction prevented inhibition of the enzyme by the copolymer. The inhibitory effect of the copolymer on alkaline phosphatase was also investigated using 113Cd NMR after exchange of the active center metal ions with 113Cd. The resulting Cd(II)6AP exhibited characteristic 113Cd resonances reflecting the environment of the A, B, and C metal binding sites of the enzyme's active center. Addition of copolymer resulted in a 113Cd NMR spectrum which indicated removal of 113Cd from the C site and formation of two distinct forms of the enzyme. Possible explanations for the 113Cd NMR results are discussed.
Asunto(s)
Fosfatasa Alcalina/análisis , Cadmio , Escherichia coli/enzimología , Maleatos/farmacología , Polietilenos/farmacología , Isótopos , Espectroscopía de Resonancia MagnéticaRESUMEN
This research evaluated the effect of an anticalculus mouthrinse, containing 3.3% pyrophosphate anion and 1.0% of a copolymer of vinylmethyl ether and maleic acid (Gantrez), on calculus formation, gingivitis, gingival recession, and epithelial attachment in beagle dogs over a one-year period of time, compared to a distilled water rinse. Each was applied twice a day for the one-year period. Compared to the control, the anticalculus mouthrinse resulted in significant reductions in the formation of calculus and gingivitis, as well as a prevention of loss of epithelial attachment in the beagle dogs. The results from this investigation suggest that it is possible to mitigate both probing epithelial attachment loss and increases in probing pocket depth at the calculus prone sites through the use of an anticalculus mouthrinse.
Asunto(s)
Cálculos Dentales/prevención & control , Difosfatos/uso terapéutico , Gingivitis/prevención & control , Maleatos/uso terapéutico , Antisépticos Bucales/uso terapéutico , Polivinilos/uso terapéutico , Análisis de Varianza , Animales , Placa Dental/prevención & control , Perros , Inserción Epitelial/patología , Recesión Gingival/prevención & control , MasculinoRESUMEN
The influence of a mouthrinse containing 0.03% triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) and 0.25% copolymer (polyvinylmethylether maleic acid copolymer), compared to a matching placebo rinse, on in vitro plaque formation was assessed in two dynamic plaque model systems. In the controlled saliva flow cell system, the triclosan-containing rinses significantly reduced total plaque compared to the placebo rinse, with no significant differences when copolymer was removed from the active rinse formula. In the continuous culture system (chemostat flow cell model), the mean plaque was significantly reduced when compared with placebo. The results of these studies indicate that a triclosan mouthrinse, in the presence or absence of copolymer, is effective in reducing plaque in vitro.
Asunto(s)
Placa Dental/microbiología , Maleatos/farmacología , Antisépticos Bucales/farmacología , Polivinilos/farmacología , Triclosán/farmacología , Bacterias/efectos de los fármacos , Células Cultivadas , Humanos , Saliva/microbiología , Análisis EspectralRESUMEN
A dentifrice containing triclosan/PVM/MA, Colgate Gum Protection Formula Toothpaste (GPF), was found to be highly effective against oral bacteria with minimal inhibitory concentration ranging from 0.3 to 5.35 micrograms/ml. A variety of in vitro model systems simulating oral environment were used to compare dentifrices containing triclosan/PVM/MA versus the dentifrices containing triclosan without PVM/MA, such as Crest Gum Health Toothpaste (CGH) and Neo-Mentadent P Toothpaste (N-MP). The uptake of triclosan on saliva-coated hydroxyapatite (HA) disks and buccal epithelial cells was significantly higher from the GPF versus the other dentifrices. Uptake on HA disks was 132 micrograms/disk versus 11 micrograms/disk from CGH; on buccal epithelial cells the uptake was 59 micrograms/2 x 10(5) cells with GPF versus 30.0 micrograms with CGH per same number of cells. The retained triclosan on the surfaces provided a sustained and higher antibacterial effect up to 4 hours post-treatment with GPF, but not with N-MP and CGH. In dynamic plaque model systems such as the chemostat or the controlled saliva flow system, GPF was significantly (P = 0.05) more effective than N-MP or CGH in reducing plaque thickness, protein and carbohydrate contents of plaque films. Collectively, the results of these microbiological and biochemical investigations indicate that the GPF has the potential to provide superior clinical efficacy versus the dentifrices without the copolymer.
Asunto(s)
Dentífricos/uso terapéutico , Maleatos/uso terapéutico , Polivinilos/uso terapéutico , Fluoruro de Sodio/uso terapéutico , Triclosán/uso terapéutico , Placa Dental/tratamiento farmacológico , Placa Dental/microbiología , Combinación de Medicamentos , Humanos , Hidroxiapatitas , Técnicas In Vitro , SalivaRESUMEN
The effect of PVM/MA copolymer on hydroxyapatite crystal growth in vitro at 37 degrees C was evaluated. The copolymer provided a 50% inhibition of the growth rate at 35 ppm for 220 minutes. The polymer adsorbed to saliva-coated hydroxyapatite disks and the adsorption was time and concentration dependent. Under exaggerated in vitro conditions, the copolymer did not etch or damage enamel surfaces at pH 5.5 and 7.5. It was highly effective against calculus formation in rats when applied topically yielding a 54% reduction (P less than or equal to 0.01). In beagle dogs, it reduced calculus formation significantly (P = 0.06) over a period of 24 to 28 weeks when applied topically either as a rinse or toothpaste. Collectively, the data indicated that the copolymer was an effective anticalculus agent when applied topically, in the presence of triclosan.
Asunto(s)
Cálculos Dentales/prevención & control , Dentífricos/uso terapéutico , Hidroxiapatitas , Maleatos/uso terapéutico , Polivinilos/uso terapéutico , Triclosán/uso terapéutico , Adsorción , Animales , Cristalización , Esmalte Dental/efectos de los fármacos , Perros , Durapatita , Humanos , Ratas , Ratas EndogámicasRESUMEN
The concentration and elimination rate of triclosan in saliva was assessed as part of a six week clinical study which evaluated the antiplaque efficacy of a 0.3% triclosan/PVM/MA copolymer/NaF dentifrice. On day one of the study the concentration of triclosan in whole saliva was determined at various times after dentifrice use for both the triclosan/PVM/MA copolymer/NaF and placebo dentifrice groups. The results indicated that the salivary triclosan levels ranged from 19.7 micrograms/ml at 5 minutes to 1 microgram/ml at 2 hours after use of the 0.3% triclosan dentifrice. The triclosan elimination curve for saliva exhibited a mono-exponential decline with a half-life of 26 minutes. The plaque content of triclosan, one hour after dentifrice use, which was determined at the end of the study, was found to be relatively high (25 micrograms/g) compared to that seen in saliva at the same time (6.2 micrograms/ml). It was concluded that the 0.3% triclosan/PVM/MA copolymer/NaF test dentifrice provided effective delivery and bioavailability of the antiplaque agent, triclosan. This was based on the relatively high salivary and plaque triclosan levels observed and the concomitant reduction in plaque formation seen at the end of the study.
Asunto(s)
Placa Dental/metabolismo , Maleatos/análisis , Éteres Fenílicos/análisis , Polivinilos/análisis , Saliva/análisis , Fluoruro de Sodio/análisis , Triclosán/análisis , Placa Dental/prevención & control , Humanos , Pastas de Dientes , Triclosán/uso terapéuticoRESUMEN
The cariostatic effectiveness of dentifrices and solutions containing sodium monofluorophosphate (MFP) was evaluated in rats. In one study using 36 CARA rats, the caries inhibiting effects of sodium fluoride and MFP solutions, at equivalent soluble fluoride concentrations (750 ppm F), were compared. Both MFP and sodium fluoride significantly (p less than 0.01) reduced smooth surface caries by 78% to 81%, respectively. No significant differences between the two treatment groups were observed. In a second study, 5 dentifrices formulated with dicalcium phosphate dihydrate (DCPD) abrasive and different amounts of MFP (0, 250, 500, 750, and 1000 ppm F) were tested for cariostatic effects in CARA rats. Compared to the control groups, the MFP/DCPD dentifrices significantly (p less than 0.01) reduced smooth surface caries incidence by 66%, 81%, 76% and 85% at the 250, 500, 750, and 1000 ppm F concentrations, respectively. In each of the studies, both enamel fluoride content and molar surface solubility were measured. A third study assessed the compatibility of MFP with different abrasives and the effect of dentifrice composition on the release of MFP from a dentifrice slurry to a saliva phase. No differences in MFP release were observed for two different silica-based formulations which differed with respect to thickener, humectants and other ingredients.