Clinical Studies of Plaque Control Agents: An Overview RALPH R. LOBENE Forsyth Dental Center, 140 The Fen way, Boston, Massachusetts
J Dent Res 58(12):2381-2388, December 1979 Dental plaque is massed packed bacterial cells which accumulate on the supra- and subgingival surfaces of the teeth as well as on the oral mucosa. The microorganisms of plaque have been shown to be associated with both dental caries and periodontal disease. This overview of clinical studies of plaque control agents reviews the properties -and effects of chemical compounds which have demonstrated a potential for the control ofplaque microorganisms. The search for clinically effective antiplaque agents has been stimulated by findings in laboratory and animal studies ofplaque dynamics. Based upon these in vitro and in vivo experiments, chemotherapeuric agents such as antibiotics, antiseptics, enzymes, detergents, bacteriosides, antimetabolites, and oxidizing agents have been evaluated against human plaque microorganisms using the ultimate biological model - man. Continued study of chemotherapeutic agents should be encouraged because many of these drugs have been shown to be safe for human use and may require only the development of a delivery system to potentiate their concentration in a specific local site. Use of these chemotherapeutic agents, which can be self-administered, becomes an attractive way of providing the public with a cost-effective method of preventing caries and periodontal disease.
Introduction. The oral health of the population of the United States in 1970 as documented by data from the National Center for Health Statistics revealed the following facts: 1. Fifty-six million teeth had been extracted; 2. thirty million people were completely edentulous; 3. twenty-five million people were 50 percent edentulous; 4. eighty percent of all adolescents suffered from gingivitis or simple periodontitis; 5. one billion carious lesions were unrestored; and 6. eighty-two million people, less than half of our population, were drinking fluoridated water. These figures reflect the unmet needs for dental services as well as the demand which has been satisified. In 1977, Americans
spent ten billion dollars to satisfy their demands for dental services, leaving a large reservoir of unmet needs. It should be obvious, but bears repetition, that a major economic impact on the public's oral health needs, wants, and demands can be achieved only by the control or prevention of the major dental diseasesnamely, caries and periodontal disease.
Primary etiology. At this time, our best information indicates that dental caries and periodontal disease are of local origin and not systemic in nature. They are essentially plaque diseases. The concept of a web of causation of dental caries has been proposed by Glass.1 It depicts multiple cross-linking of numerous factors such as nutrition, diet, trace elements, geography, race, education, economics, sucrose, fluorides, oral flora, hygiene, and plaque. Newbrun has recently summarized the abundant literature on the epidemiology and research in caries which describes these complex interrelationships.2 Oral microorganisms have long been assigned an important role in the caries process. It was Keyes, however, working with experimental animal models, who demonstrated the infectious and transmissible nature of dental caries, implicating as the primary etiologic agent3 an oral flora sensitive to antibiotics. Host and functional factors, as well as local factors, are implicated in the etiology of gingivitis, the simplest reversible form of periodontal disease. Unresolved gingivitis can become periodontitis with the destruction of the supporting periodontal tissues, which are the ultimate barometer of periodontal health. Current evidence indicates that the local environment, which is dominated by plaque microorganisms, is the primary etiologic factor in periodontal disease. This holds true for the nonspecific 2381
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plaque hypothesis as proposed by Loesche,4 as well as the hypothesis of bacterial specificity in destructive periodontal disease as postulated by Socransky5 and others.6,7 Accepting microorganisms as the primary etiologic factor for both caries and periodontal disease, the rationale for the prevention and control of these diseases is the daily systematic and thorough deplaquing of the oral cavity. For this purpose, mechanical cleaning has broad appeal because it is self-administered and, when appropriately practiced, is non-invasive of oral tissues. Both short- and long-term studies of a variety of oral hygiene procedures have demonstrated that it is possible to prevent or control both caries8 and gingivitis.9,10,11 However, the effective practice of oral hygiene is frequently influenced by motivation, socioeconomic status, manual dexterity, and knowledge of the true value of scrupulously clean teeth. In the continuing search for an answer to plaque control, the use of chemotherapeutic agents coupled with a variety of delivery systems offers the potential for safe, simple, and economical prevention of major dental infections.
Dental plaque. The initial event in the in vivo formation of plaque occurs at the interface formed by the tooth surface and saliva. A structureless organic matrix or pellicle forms, which is probably the end product of the interaction of salivary mucins, glycoproteins, lipids, and serum albumin.1 2 This pellicle, which is approximately 15, thick, forms a new interface with the tooth surface and the gingival crevice. For the first few hours, it can remain almost free of microorganisms.1 3 These are immature plaques, mostly streptococci surrounded by large halos, which coalesce with one another. Extracellular material, proved to be mucopolysaccharide dextrans, has been implicated as the mechanism for the attachment of microorganisms to the tooth surface. While filamentous organisms are found in plaque, they are scarce at this early stage of development.14 In addition to microorganisms, desquamated epithelial cells and leukocytes are also present. Five-day-old plaque reaches a thickness of approximately 60,u, and thus presents yet a new interface to the saliva
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and gingival crevice. Age changes in plaque composition grown in culture media have been described by Ritz.15 Young one-day-old plaque showed streptococci, neisserae, and nocardia; on the ninth day, streptococci were still found, but the predominant microbiota were actinomy ces, veillonellae, and corynebacteria, with some fusobacteria also present. Loe et al. showed similar growth patterns in vivo following the withdrawal of all oral hygiene.9 By the ninth day in this human study, spirillae and spirochetes were also seen. Different sites in the oral cavity have been demonstrated to harbor different microorganisms. For example, S. salivarius is found on the tongue, S. mutans and S. sanguis on smooth tooth surfaces, and A. naeslundii on root surfaces. On the other hand, spirochetes and B. melaninogenicus are found in the gingival crevice. In addition to localization of bacteria, qualitative and quantitative changes in the microbiota repeatedly harvested from the same site in the same individual have been reported. 16 The qualitative make-up of plaque as well as the number of bacterial cells present can affect the severity of the dental diseases. The cell count of plaque from a gingival pocket averages 2.1 X 1011 microorganisms per gram of wet weight. Theoretically, if a single microorganism is assumed to have the dimensions of one cubic micron, one gram of wet weight plaque would contain 1 X 101 2 microorganisms. Therefore, plaque is massed, packed bacterial cells, and it is the need to effectively disrupt the daily accumulation of these oral microorganisms on oral tissues which fuels the search for better preventive methods.
Laboratory and animal trials. Our search for antiplaque agents was stimulated by the findings of laboratory and animal studies of plaque dynamics. Krasse17 and Gibbons18 found rodent and human streptococci capable of producing extracellular polysaccharides in sucrose broth cultures. These studies showed gelatinous masses of bacteria adhering to the culture vessels, suggesting that dextranlike polymers might be the mechanism for bacterial attachment to teeth. The presence
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of extracellular polysaccharides has also been demonstrated in human dental plaque. Carlsson and Egelberg19 showed that a high content of sucrose in the diet stimulates the same type of plaque formation in man and suggested that restricting the intake of sucrose could retard plaque formation. Up to this point, salivary microorganisms and sucrose have been linked together. Subsequently, Gibbons and Nygaard2° found that the addition of low molecular weight dextrans to culture media prevented the development of plaque-like deposits in sucrose-rich broth cultures of plaque microorganisms. These findings prompted Gibbons and Keyes2l to add low molecular weight dextrans to the diet and water supply of experimental hamsters. The control animals developed subgingival plaque and bone loss. Concentrations of dextrans as low as six percent in the experimental group prevented the formation of gelatinous plaques on teeth and also prevented loss of supporting bone. In related animal experiments, Fitzgerald et al.22 demonstrated the activity of dextranase in preventing plaque growth. The enzyme isolated from penicillium funiculosum was successfully used in hamsters to prevent plaque formation and dental caries. Since microorganisms have been consistently implicated in the cause of dental caries and periodontal disease, the discovery by Keyes,3 that animal caries were infectious and transmissible, logically led to the use of antibiotics for the control of plaque. Using penicillin, Shaw2 3 and Keyes3 demonstrated that this control was possible. More important was their finding that it was possible to use antibiotics for as short a duration as one week to reduce plaque and dental disease for up to four months in laboratory animals. 2 42 5
Clinical trials. These examples of in vitro and in vivo experimental studies served as a stimulus for human clinical trials of chemotherapeutic agents for the control and prevention of plaque because, in the final analysis, the effects of any preventive agent must be confirmed in the ultimate biologic modelman. Following the leads from these animal studies, a series of short-term clinical trials was conducted to determine the effect of low molecular weight dextrans on human
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plaque. A dextran of approximately 20,000 in molecular weight was used at concentrations of two and 20 percent.26 The two percent dextran in a five percent sucrose solution was used as a mouth rinse in the absence of all oral hygiene. Total exposure time was 14 minutes in divided doses of two minutes each. The effect, as measured using a plaque index scoring of the buccal and lingual surfaces of all teeth, showed no differences between the placebo and active mouthwashes at the end of the three-day no-brushing regimen. Subsequently, the concentration of dextran was increased to 20 percent and incorporated into sucrose troches. Exposure time of plaque to the dextran was increased to approximately ten hours' contact, compared to 14 minutes in the previous study. Despite the increased exposure time and concentration, no consistent effects of low molecular weight dextran were demonstrated on plaque growth or on the bacterial composition of plaque. These negative results should not be considered conclusive. The use of dextrans deserves further investigation for several reasons. Only one dextran has been investigated, and there are many others which may have the desired effect of reducing human plaque growth. This agent has great appeal for human use because dextrans are nontoxic-routinely used as food additives and blood plasma extenders. Dextrans are found in natural sugars and are removed with great difficulty during the refining of sugar. Considering the relationship between plaque, sucrose, and dental caries, an additive compatible with sucrose which would reduce its cariogenicity becomes an intriguing approach to plaque control. In another approach to alteration of plaque, one which did not disrupt the metabolic pathways of the microorganisms by supplying a dextran substrate, the enzyme dextranase was used to reduce the formation of plaque much in the same way that Fitzgerald et al. had used dextranase in animals. The efficacy of the dextranase was attributed to the degradation of the extracellular dextrans by which plaque microorganisms attach to tooth surfaces. In no-brushing clinical trials, a total of 320,000 units of dextranase was used daily for three days in divided doses as a mouthwash.2 7 Plaque was treated with the enzyme for a period of 24 minutes daily. Clinical plaque scores were not
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significantly different for the active and placebo solutions. Harvested dried plaque weights (which estimate plaque mass) showed a significant reduction in human plaque with the use of this enzyme when all other oral hygiene procedures had been eliminated. Other investigators using dextranase for the control of human plaque did not demonstrate an effect on plaque.28 Considering the complexity of the oral microflora and the fact that specific organisms are found in specific locales in the oral cavity, it is not likely that the use of a single enzyme will effectively control plaque. Evidence exists to indicate that levanase and lipase may also play a role in plaque reduction. If the use of enzymes is to succeed, it seems reasonable to predict it will be an "enzyme cocktail." If caries and periodontal disease are infections and transmissible diseases caused by microorganisms, they may be amenable to short-term treatment with broad-spectrum antibiotics to achieve extended suppression of the oral flora. In a study by Mitchell and Holms,29 vancomycin was applied topically once a day for eight days to the teeth of mentally retarded children who had large amounts of plaque and severe gingivitis. Over the next 22 days, these patients who could not practice oral hygiene received no further treatment. For most subjects, limited use of vancomycin produced a suppression of plaque which persisted to the end of the study. Jordan and DePaola30 used a three percent vancomycin gel and studied the topical effects on Streptococcus mu tans in dental plaque. Children were fitted with custom-made mouth trays and treated with the gel for ten minutes once a day for a period of five days. Plaque was monitored for S. mutans which was suppressed in both sound and carious fissures for as long as three weeks posttreatment. Antibiotics such as vancomycin and kanamycin have the advantage of not being absorbed from the intestine, which limits their use in general medicine, but enhances their potential use in dentistry. Based upon the carryover effect of antibiotics demonstrated by Keyes and Shaw in animal studies, we elected to investigate the short-term use of erythromycin in the human model because of the relatively small risk in the face of the potential benefits to be derived by changing the patho-
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genicity of plaque. The effect of erythromycin on plaque formation during and after use was studied.31 The fate of spirochetes, oral streptococci, and extracellular polysaccharide-forming microorganisms which have been implicated in the etiology of both caries and periodontal disease was also followed throughout the experiment. The amount of plaque, as determined by harvesting, drying, and weighing, was measured weekly during a three-week period of normal brushing, followed by a similar period of no brushing. Erythromycin as a liquid suspension was then used as a mouthwash for one week, four times daily, for three minutes and swallowed. Total dose was one gram per day. Throughout the entire experiment, subjects did not practice conventional mechanical cleansing of the oral cavity. Following the use of the antibiotic weekly, plaque accumulation was measured for five weeks. Comparison of the baseline brushing and no-brushing periods indicated that four times as much plaque accumulated during the no-brushing period as during the brushing period. Use of the antibiotic erythromycin reduced plaque by 35 percent compared to the formation in the nobrushing period. However, the use of the antibiotic alone was not as effective as brushing in reducing the accumulation of plaque. After withdrawal of the antibiotic, the accumulation of plaque was as high as after the no-brushing period, so that the carryover effect, which had been demonstrated in experimental animals, was not seen in humans. In addition, there were no dramatic effects of the drug on streptococci or polysaccharide-forming microorganisms. The only positive effect of the antibiotic was on spirochetes, which were present in all subjects at the outset of the study, but which did not reappear in the oral flora for 18 weeks after the administration of erythromycin. The topical short-term use of broad-spectrum antibiotics to control plaque does not appear to be a practical approach to plaque control when measured against the use of these chemotherapeutic agents to fight life-threatening infections. A more practical approach to the control of plaque would be the use of powerful bacteriocidal or bacteriostatic chemicals which are riot used to treat other infectious
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diseases. The bisbiguanides are a series of compounds which have demonstrated superior antimicrobial properties.32 Alexidine (2 ethylhexyl bisbiguanidine dihydrochloride), which belongs to the same family of chemical compounds as chlorhexidine, has been shown to be highly effective in inhibiting plaque formation and preventing gingivitis in rats and hamsters. The drug is of low oral toxicity and poorly absorbed from the gastrointestinal tract. It is active against pathogenic yeasts, thus virtually eliminating the possibility of the development of moniliasis with continued use. In limited human use, alexidine-resistant strains of microorganisms have not emerged. A group of short-term, no-brushing cross-over clinical trials evaluated mouthwashes containing alexidine in a concentration of 0.035-0.05 percent.33-35 The antimicrobial rinse was used for one minute, either once or twice daily, for a period of two weeks. All studies reported a significant reduction in plaque and gingivitis. Several clinical trials of six months' duration have demonstrated similar findings when alexidine was used as a mouthwash to supplement routine daily oral hygiene procedures.3 6-39 These studies included children and young adults, the groups that would benefit most from the potential for the prevention of oral disease demonstrated with the use of alexidine. In these studies, the beneficial effect on oral health of the chemotherapeutic agents was superimposed upon the benefits already gained from the practice of normal oral hygiene. Side effects have been few except for the occurrence of a transient extrinsic brown stain on the tongue, teeth, and occasionally the oral mucosa. These teeth stains were easily removed by simple prophylaxis. To date, the bisbiguanides have shown the most promising potential for the therapeutic control of dental plaque and the plaquerelated diseases. As indicated previously, the initial step in the formation of plaque on a freshly cleansed tooth surface is the sorption of salivary proteins to enamel. A number of surfactants have been investigated to determine their ability to alter the wettability of enamel and the sorption of proteins, and consequently to affect plaque formation on tooth surfaces.40 Usdin et al.41 immersed
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human enamel in dilute solutions of pyromellitic acid (1, 2, 4, 5, benzenetetracarboxilic acid) and reduced protein sorbtion from whole saliva by 58 percent. This finding prompted the use of pyromellitic acid in a clinical trial because it is relatively nontoxic. Interestingly, when added to cultures of microorganisms, it did not prevent bacterial growth. This might be an advantage in that the beneficial elements of the local environment could be preserved. In a threeday, no-brushing study, plaque accumulation following a prophylaxis was significantly reduced using a pyromellitic acid mouthwash, compared to the results of a placebo treatment.42 In a two-week brushing study in which subjects used a liquid pyromellitic acid dentifrice twice daily, a similar reduction in plaque accumulation was found.43 These studies are encouraging because they have demonstrated a reduction in plaque by altering the interface of the tooth with saliva, rather than temporarily killing oral bacteria which may be harmless or beneficial, as well as those which are pathogenic. Other surface active agents such as cetylpyridinium chloride (CPC) have been available and used in mouthwashes for many years. Clinical trials in humans have demonstrated the beneficial effects of CPC for reducing plaque and gingivitis with and without the practice of toothbrushing.4446 In a study involving 60 subjects, the effect of CPC at concentrations of 1:1000 and 1:2000 on gingivitis plaque, plaque pH and plaque flora were studied over a 21-day period of use.47 Subjects practiced customary toothbrushing and rinsed with 20 ml of CPC for 20 seconds, twice daily, for 21 days. At both concentrations of CPC, gingivitis was significantly reduced by 40 percent. As measured by dry weight, plaque was also reduced for the CPC groups. Microbiological assays for total aerobes, anaerobes and streptococci were significantly reduced as were counts for Streptococcus mutans during the 21 days the drug was used. All bacterial cell counts returned to near normal levels seven days after the CPC rinses were discontinued. Interestingly, CPC users showed more extrinsic stain than the placebo group. More recently, a six-month clinical trial which studied the effect of the daily use of CPC mouthwashes on plaque and gingivitis was completed. In this longer
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term trial, both plaque and gingivitis
scores
significantly reduced in the CPC groups. 48 Other compounds which have demonstrated activity against plaque and gingivitis are the organic amine fluorides.49-51 While these compounds are known to have bacteriostatic activity against plaque, they have also been shown to reduce caries by approximately 35 percent when incorporated into a dentifrice.52 The mechanism of action is postulated to be due to fluoride uptake by hydroxyapatite, blocking of bacterial enzyme systems, and surfactant action which enhances cell uptake of the amine fluorides. These compounds are interesting because of their potential "double barrel" clinical effect in reducing both were
caries and
gingivitis.
Chemicals such as oxidizing and reducing agents, antiseptics, antimicrobials, alkalizers, and bleaching agents have also been investigated for their antiplaque properties. However, they have not been used long enough to determine their true worth for the control or prevention of dental disease. The continual study of these chemotherapeutic agents should be encouraged because many of these drugs have been shown to be safe for human use. These drugs may have been shelved simply because an effective delivery system has not been developed which will localize the drug to a specific site, control its release, and potentiate its action. Another symposium on controlled and sustained release agents in dentistry, held at this meeting, reported several new practical approaches to the delivery of drugs to sites where the tooth, acquired pellicle and gingival epithelium interface. In approaching this problem, Katz and Park53 have proposed a system of "enamel conditioning," which would enhance the incorporation of antiplaque agents into enamel by first treating enamel with a mild chelating agent. The slightly decalcified enamel is then immediately treated with a reprecipitating agent such as stannous fluoride, since it contains an antimicrobial agent which becomes trapped in the reconstituted enamel. They found that enamel treated with compounds like hexachlorophene and fluorophene very effectively resisted in vitro plaque formation. Moreno et al.54 have found in recent studies that the acquired pellicle of enamel in fluoridated areas
differs from that in nonfluoridated areas. Their findings suggest that the cariostatic effect of fluoride may be due to a change in the composition of the pellicle formed in these different areas as well as the incorporation of fluoride into hydroxyapatite. These examples of new approaches to the enhancement of the chemotherapeutic effects of antiplaque agents suggest that now may be the time to go to the shelf and re-evaluate some of our old safe drugs.
Conclusions. Our current knowledge of dental caries and periodontal disease has identified microorganisms which are localized in specific sites on the enamel, in the gingival crevice, and on the root surface. The chemotherapeutic approach to plaque control continues to have great appeal, because it may be possible to treat these specific sites for a short, controlled period of time with drugs that are highly toxic to the microorganisms. Using an appropriately designed delivery system, this method would provide optimum benefits at minimum risks to the patient. If these drugs were capable of being safely self-administered, it would enhance their cost effectiveness. In lieu of a major breakthrough in drug therapy for control or prevention of dental disease, we must rely on the motivation of people to place good oral health high on their list of priorities.5 5 Since this is not readily happening, next to fluoridation of all public water supplies, the most attractive option we have for the prevention of dental disease is continued research in chemotherapeutics for plaque control. REFERENCES 1. GLASS, R.L.: Personal communication, 1975. 2. NEWBRUN, E.: Cariology, Baltimore: Williams and Wilkins, 1978. 3. KEYES, P. H.: The Infectious and Transmissible Nature of Experimental Dental Caries. Findings and Implications, Arch Oral Biol 1:304-320, 1960. 4. LOESCHE, W. J.: Chemotherapy of Dental Plaque Infections, Oral Sci Rev 9:65-107, 1979. 5. SOCRANSKY, S. S.: Microbiology of Periodontal Disease-Present Status and Future Considerations, J Periodontol 48:497-504, 1977. 6. NEWMAN, M. G.; SOCRANSKY, S. S.; SAVITT, E. D.; PROPAS, D. A.; and CRAW-
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FORD, A.: Studies of the Microbiology of Periodontitis, J Periodontol 47:373-379, 1976. NEWMAN, M. G. and SOCRANSKY, S. S.: Predominant Cultivable Microbiota in Periodontosis, J Periodont Res 12:120-128, 1977. AXELSSON, P. and LINDHE, J.: The Effect of a Preventive Program on Dental Plaque, Gingivitis and Caries in School Children. Results after One and Two Years, J Clin Periodontol 1:126-138, 1974. LOE, H.; THEILADE, E.; and JENSEN, S. B.: Experimental Gingivitis in Man, J Periodontol 36:177-187, 1965. SUOMI, J. D.; GREENE, J. C.; VERMILLION, J. R.; DOYLE, J.; CHANG, J. J.; and LEATHERWOOD, E. C.: The Effect of Controlled Oral Hygiene Procedures on the Progression of Periodontal Disease in Adults: Results after Third and Final Year, JPeriodontol 42:152-160, 1971. LIGHTNER, L. M.;O'LEARY, T. J.; DRAKE, R. B.; CRUMP, P. P.; and ALLEN, M. F.: Preventive Periodontic Treatment Procedures: Results over 46 Months, J Periodontol 42: 555-561, 1971. MECKEL, A. H.: The Formation and Properties of Organic Films on Teeth, Arch Oral Biol 10:585-589, 1965. McDOUGALL, W. A.: Studies on Dental Plaque. II. The Histology of Dental Plaque and its Attachment, Australian Dent J 8: 398407, 1963. MANDEL, I. D.: Dental Plaque: Nature, Formation and Effects, J Periodontol 37: 357-367, 1966. RITZ, H. L.: Microbial Population Shift in Developing Human Dental Plaque, Arch Oral Biol 12:1561-1568, 1967. SOCRANSKY, S. S.: Relationship of Bacteria to the Etiology of Periodontal Disease, J Dent Res (Supplement to No. 2) 49:203222, 1970. KRASSE, B.: Human Streptococci and Experimental Caries in Hamsters, Arch Oral Biol 11:429436, 1966. GIBBONS, R. J. and BANGHART, S.: Synthesis of Extracellular Dextran by Cariogenic Bacteria and its Presence in Human Dental Plaque, Arch Oral Biol 12:11-24, 1967. CARLSSON, J. and EGELBERG, J.: Effect of Diet on Early Plaque Formation in Man, Odont Rev 16:112-125, 1965. GIBBONS, R. J. and NYGAARD, M.: Synthesis of Insoluble Dextran and its Significance in the Formation of Gelatinous Deposits by Plaque-forming Streptococci, Archs Oral Biol 13:1249-1262, 1968. GIBBONS, R. J. and KEYES, P. H.: Inhibition of Insoluble Dextran Synthesis, Plaque Formation, and Dental Caries in Hamsters
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tudinal Effect of an Antibacterial Mouth- 46. CIANCIO, S. G.; MATHER, B. S.; and wash on Gingivitis and Dental Plaque, IADR BRUNNEL, H. L.: The Effect of a QuaterProgr & Abst 53:No. 364, 1974. nary Ammonium-containing Mouthwash on LOBENE, R. R. and SOPARKAR, P. M.: Formed Plaque, Pharmacol Ther Dent 3: A Clinical Trial of the Effect of Alexidine 1-6, 1978. Mouthwash on Plaque and Gingivitis, IADR 47. LOBENE, R. R.; KASHKET, S.; SOPARKAR, Progr & Abst 55:No. 802, 1976. P. M.; SHLOSS, J.; and SABINE, S.: The Effect of Cetylpyridinium Chloride on SPOLSKY, V. W. and FORSYTHE, A. B.: Human Plaque and Gingivitis, AADR Progr & Effects of Alexidine 2 HC1 Mouthwash on Abst 58:No. 487, 1978. Plaque and Gingivitis after Six Months, 48. LOBENE, R. R. and SOPARKAR, P. M.: JDent Res 56:1349-1358, 1977. The Effect of Cetylpyridinium Chloride WEATHERFORD, T. W.; FINN, S. B.; and Mouthwash on Human Plaque and Gingivitis, JAMISON, H. C.: Effects of Alexidine on AADRProgr& Abst 56:No. 575, 1977. Plaque and Gingivitis in Humans over a 49. DOLAN, M. M.; KAVANAGH, B. J.; and Six-month Period, JADA 94:528-536, 1977. YANKELL, S. L.: Artificial Plaque PrevenBAKER, P. J.; COBURN, R. A.; GENCO, R. J.; and EVANS, R. T.: The in vitro Inhibition with Organic Fluorides, J Periodontol tion of Microbial Growth and Plaque Forma43:561-563, 1972. tion by Surfactant Drugs, J Periodontol Res 50. SHERN, R.; SWING, K. W.; CRAWFORD, J. J.: Prevention of Plaque Formation by 13:474485, 1978. Organic Formation by Organic Fluorides, USDIN, V.; McMAHON, R.; and FELGER, J Oral Med 25:93-97, 1970. C.: Inhibition of Protein Sorption to Enamel, IADR Progr & Abst 51:No. 306, 51. LOBENE, R. R. and SOPARKAR, P. M.: The Effect of Amine Fluorides on Human 1972. Plaque and Gingivitis, IADR Progr & Abst LOBENE, R. R. and SOPARKAR, P. M.: 53:No. 369, 1974. A Clinical Study of Antiplaque Agents, 52. MARTHALER, T. M.: Caries Inhibition after JPeriodontol 45:561-563, 1974. Seven Years' Use of an Amine Fluoride USDIN, V. P.; McMAHON, R.; SOPARKAR, P. M.; and LOBENE, R. R.: Laboratory and Dentifrice, Br Dent J 124:510-515, 1968. Clinical Studies Relating Amylase Sorption 53. KATZ, S. and PARK, K.: Enhancement and Plaque Accumulation, IADR Progr & of the Antiplaque Value of Antibacterial Abst 53:No. 280, 1974. Agents by Enamel-conditioning Methods. HOLBECHE, J. D.; RULJANCICH, M. K.; I. Rationale, Mechanism and Initial Findings, and READE, P. C.: A Clinical Trial of the JDent Res 54:540-547, 1975. Efficacy of a Cetylpyridinium Chloride-based 54. MORENO, E. C.; KRESKA, M.; and HAY, Mouthwash. I. Effect on Plaque AccumulaD. I.: Adsorption of Two Human Parotid tion and Gingival Condition, Australian Dent Salivary Macromolecules on Hydroxy-, FluorJ 20:397404, 1975. hydroxy-, and Fluorapatites, Arch Oral Biol 23:5 25-533, 1978. CIANCIO, S. G.; MATHER, M. L.; and BRUNNELL, H. L.: Clinical Evaluation of a 55. SHULMAN, J.: Current Concepts of Patient Quaternary Ammonium-containing MouthMotivation Toward Long-term Oral Hygiene: A Literature Review, JASPD 4:7-10, 1974. rinse, J Periodontol46:397-400, 1975.
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J Dent Res 58(12):2381-2388, December 1979 Dental plaque is massed packed bacterial cells which accumulate on the supra- and subgingival surfaces of the teeth as well as on the oral mucosa. The microorganisms of plaque have been shown to be associated with both dental caries and periodontal disease. This overview of clinical studies of plaque control agents reviews the properties -and effects of chemical compounds which have demonstrated a potential for the control ofplaque microorganisms. The search for clinically effective antiplaque agents has been stimulated by findings in laboratory and animal studies ofplaque dynamics. Based upon these in vitro and in vivo experiments, chemotherapeuric agents such as antibiotics, antiseptics, enzymes, detergents, bacteriosides, antimetabolites, and oxidizing agents have been evaluated against human plaque microorganisms using the ultimate biological model - man. Continued study of chemotherapeutic agents should be encouraged because many of these drugs have been shown to be safe for human use and may require only the development of a delivery system to potentiate their concentration in a specific local site. Use of these chemotherapeutic agents, which can be self-administered, becomes an attractive way of providing the public with a cost-effective method of preventing caries and periodontal disease.
Introduction. The oral health of the population of the United States in 1970 as documented by data from the National Center for Health Statistics revealed the following facts: 1. Fifty-six million teeth had been extracted; 2. thirty million people were completely edentulous; 3. twenty-five million people were 50 percent edentulous; 4. eighty percent of all adolescents suffered from gingivitis or simple periodontitis; 5. one billion carious lesions were unrestored; and 6. eighty-two million people, less than half of our population, were drinking fluoridated water. These figures reflect the unmet needs for dental services as well as the demand which has been satisified. In 1977, Americans
spent ten billion dollars to satisfy their demands for dental services, leaving a large reservoir of unmet needs. It should be obvious, but bears repetition, that a major economic impact on the public's oral health needs, wants, and demands can be achieved only by the control or prevention of the major dental diseasesnamely, caries and periodontal disease.
Primary etiology. At this time, our best information indicates that dental caries and periodontal disease are of local origin and not systemic in nature. They are essentially plaque diseases. The concept of a web of causation of dental caries has been proposed by Glass.1 It depicts multiple cross-linking of numerous factors such as nutrition, diet, trace elements, geography, race, education, economics, sucrose, fluorides, oral flora, hygiene, and plaque. Newbrun has recently summarized the abundant literature on the epidemiology and research in caries which describes these complex interrelationships.2 Oral microorganisms have long been assigned an important role in the caries process. It was Keyes, however, working with experimental animal models, who demonstrated the infectious and transmissible nature of dental caries, implicating as the primary etiologic agent3 an oral flora sensitive to antibiotics. Host and functional factors, as well as local factors, are implicated in the etiology of gingivitis, the simplest reversible form of periodontal disease. Unresolved gingivitis can become periodontitis with the destruction of the supporting periodontal tissues, which are the ultimate barometer of periodontal health. Current evidence indicates that the local environment, which is dominated by plaque microorganisms, is the primary etiologic factor in periodontal disease. This holds true for the nonspecific 2381
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plaque hypothesis as proposed by Loesche,4 as well as the hypothesis of bacterial specificity in destructive periodontal disease as postulated by Socransky5 and others.6,7 Accepting microorganisms as the primary etiologic factor for both caries and periodontal disease, the rationale for the prevention and control of these diseases is the daily systematic and thorough deplaquing of the oral cavity. For this purpose, mechanical cleaning has broad appeal because it is self-administered and, when appropriately practiced, is non-invasive of oral tissues. Both short- and long-term studies of a variety of oral hygiene procedures have demonstrated that it is possible to prevent or control both caries8 and gingivitis.9,10,11 However, the effective practice of oral hygiene is frequently influenced by motivation, socioeconomic status, manual dexterity, and knowledge of the true value of scrupulously clean teeth. In the continuing search for an answer to plaque control, the use of chemotherapeutic agents coupled with a variety of delivery systems offers the potential for safe, simple, and economical prevention of major dental infections.
Dental plaque. The initial event in the in vivo formation of plaque occurs at the interface formed by the tooth surface and saliva. A structureless organic matrix or pellicle forms, which is probably the end product of the interaction of salivary mucins, glycoproteins, lipids, and serum albumin.1 2 This pellicle, which is approximately 15, thick, forms a new interface with the tooth surface and the gingival crevice. For the first few hours, it can remain almost free of microorganisms.1 3 These are immature plaques, mostly streptococci surrounded by large halos, which coalesce with one another. Extracellular material, proved to be mucopolysaccharide dextrans, has been implicated as the mechanism for the attachment of microorganisms to the tooth surface. While filamentous organisms are found in plaque, they are scarce at this early stage of development.14 In addition to microorganisms, desquamated epithelial cells and leukocytes are also present. Five-day-old plaque reaches a thickness of approximately 60,u, and thus presents yet a new interface to the saliva
JDent Res December 1979
and gingival crevice. Age changes in plaque composition grown in culture media have been described by Ritz.15 Young one-day-old plaque showed streptococci, neisserae, and nocardia; on the ninth day, streptococci were still found, but the predominant microbiota were actinomy ces, veillonellae, and corynebacteria, with some fusobacteria also present. Loe et al. showed similar growth patterns in vivo following the withdrawal of all oral hygiene.9 By the ninth day in this human study, spirillae and spirochetes were also seen. Different sites in the oral cavity have been demonstrated to harbor different microorganisms. For example, S. salivarius is found on the tongue, S. mutans and S. sanguis on smooth tooth surfaces, and A. naeslundii on root surfaces. On the other hand, spirochetes and B. melaninogenicus are found in the gingival crevice. In addition to localization of bacteria, qualitative and quantitative changes in the microbiota repeatedly harvested from the same site in the same individual have been reported. 16 The qualitative make-up of plaque as well as the number of bacterial cells present can affect the severity of the dental diseases. The cell count of plaque from a gingival pocket averages 2.1 X 1011 microorganisms per gram of wet weight. Theoretically, if a single microorganism is assumed to have the dimensions of one cubic micron, one gram of wet weight plaque would contain 1 X 101 2 microorganisms. Therefore, plaque is massed, packed bacterial cells, and it is the need to effectively disrupt the daily accumulation of these oral microorganisms on oral tissues which fuels the search for better preventive methods.
Laboratory and animal trials. Our search for antiplaque agents was stimulated by the findings of laboratory and animal studies of plaque dynamics. Krasse17 and Gibbons18 found rodent and human streptococci capable of producing extracellular polysaccharides in sucrose broth cultures. These studies showed gelatinous masses of bacteria adhering to the culture vessels, suggesting that dextranlike polymers might be the mechanism for bacterial attachment to teeth. The presence
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of extracellular polysaccharides has also been demonstrated in human dental plaque. Carlsson and Egelberg19 showed that a high content of sucrose in the diet stimulates the same type of plaque formation in man and suggested that restricting the intake of sucrose could retard plaque formation. Up to this point, salivary microorganisms and sucrose have been linked together. Subsequently, Gibbons and Nygaard2° found that the addition of low molecular weight dextrans to culture media prevented the development of plaque-like deposits in sucrose-rich broth cultures of plaque microorganisms. These findings prompted Gibbons and Keyes2l to add low molecular weight dextrans to the diet and water supply of experimental hamsters. The control animals developed subgingival plaque and bone loss. Concentrations of dextrans as low as six percent in the experimental group prevented the formation of gelatinous plaques on teeth and also prevented loss of supporting bone. In related animal experiments, Fitzgerald et al.22 demonstrated the activity of dextranase in preventing plaque growth. The enzyme isolated from penicillium funiculosum was successfully used in hamsters to prevent plaque formation and dental caries. Since microorganisms have been consistently implicated in the cause of dental caries and periodontal disease, the discovery by Keyes,3 that animal caries were infectious and transmissible, logically led to the use of antibiotics for the control of plaque. Using penicillin, Shaw2 3 and Keyes3 demonstrated that this control was possible. More important was their finding that it was possible to use antibiotics for as short a duration as one week to reduce plaque and dental disease for up to four months in laboratory animals. 2 42 5
Clinical trials. These examples of in vitro and in vivo experimental studies served as a stimulus for human clinical trials of chemotherapeutic agents for the control and prevention of plaque because, in the final analysis, the effects of any preventive agent must be confirmed in the ultimate biologic modelman. Following the leads from these animal studies, a series of short-term clinical trials was conducted to determine the effect of low molecular weight dextrans on human
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plaque. A dextran of approximately 20,000 in molecular weight was used at concentrations of two and 20 percent.26 The two percent dextran in a five percent sucrose solution was used as a mouth rinse in the absence of all oral hygiene. Total exposure time was 14 minutes in divided doses of two minutes each. The effect, as measured using a plaque index scoring of the buccal and lingual surfaces of all teeth, showed no differences between the placebo and active mouthwashes at the end of the three-day no-brushing regimen. Subsequently, the concentration of dextran was increased to 20 percent and incorporated into sucrose troches. Exposure time of plaque to the dextran was increased to approximately ten hours' contact, compared to 14 minutes in the previous study. Despite the increased exposure time and concentration, no consistent effects of low molecular weight dextran were demonstrated on plaque growth or on the bacterial composition of plaque. These negative results should not be considered conclusive. The use of dextrans deserves further investigation for several reasons. Only one dextran has been investigated, and there are many others which may have the desired effect of reducing human plaque growth. This agent has great appeal for human use because dextrans are nontoxic-routinely used as food additives and blood plasma extenders. Dextrans are found in natural sugars and are removed with great difficulty during the refining of sugar. Considering the relationship between plaque, sucrose, and dental caries, an additive compatible with sucrose which would reduce its cariogenicity becomes an intriguing approach to plaque control. In another approach to alteration of plaque, one which did not disrupt the metabolic pathways of the microorganisms by supplying a dextran substrate, the enzyme dextranase was used to reduce the formation of plaque much in the same way that Fitzgerald et al. had used dextranase in animals. The efficacy of the dextranase was attributed to the degradation of the extracellular dextrans by which plaque microorganisms attach to tooth surfaces. In no-brushing clinical trials, a total of 320,000 units of dextranase was used daily for three days in divided doses as a mouthwash.2 7 Plaque was treated with the enzyme for a period of 24 minutes daily. Clinical plaque scores were not
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significantly different for the active and placebo solutions. Harvested dried plaque weights (which estimate plaque mass) showed a significant reduction in human plaque with the use of this enzyme when all other oral hygiene procedures had been eliminated. Other investigators using dextranase for the control of human plaque did not demonstrate an effect on plaque.28 Considering the complexity of the oral microflora and the fact that specific organisms are found in specific locales in the oral cavity, it is not likely that the use of a single enzyme will effectively control plaque. Evidence exists to indicate that levanase and lipase may also play a role in plaque reduction. If the use of enzymes is to succeed, it seems reasonable to predict it will be an "enzyme cocktail." If caries and periodontal disease are infections and transmissible diseases caused by microorganisms, they may be amenable to short-term treatment with broad-spectrum antibiotics to achieve extended suppression of the oral flora. In a study by Mitchell and Holms,29 vancomycin was applied topically once a day for eight days to the teeth of mentally retarded children who had large amounts of plaque and severe gingivitis. Over the next 22 days, these patients who could not practice oral hygiene received no further treatment. For most subjects, limited use of vancomycin produced a suppression of plaque which persisted to the end of the study. Jordan and DePaola30 used a three percent vancomycin gel and studied the topical effects on Streptococcus mu tans in dental plaque. Children were fitted with custom-made mouth trays and treated with the gel for ten minutes once a day for a period of five days. Plaque was monitored for S. mutans which was suppressed in both sound and carious fissures for as long as three weeks posttreatment. Antibiotics such as vancomycin and kanamycin have the advantage of not being absorbed from the intestine, which limits their use in general medicine, but enhances their potential use in dentistry. Based upon the carryover effect of antibiotics demonstrated by Keyes and Shaw in animal studies, we elected to investigate the short-term use of erythromycin in the human model because of the relatively small risk in the face of the potential benefits to be derived by changing the patho-
J Dent Res December 19 79
genicity of plaque. The effect of erythromycin on plaque formation during and after use was studied.31 The fate of spirochetes, oral streptococci, and extracellular polysaccharide-forming microorganisms which have been implicated in the etiology of both caries and periodontal disease was also followed throughout the experiment. The amount of plaque, as determined by harvesting, drying, and weighing, was measured weekly during a three-week period of normal brushing, followed by a similar period of no brushing. Erythromycin as a liquid suspension was then used as a mouthwash for one week, four times daily, for three minutes and swallowed. Total dose was one gram per day. Throughout the entire experiment, subjects did not practice conventional mechanical cleansing of the oral cavity. Following the use of the antibiotic weekly, plaque accumulation was measured for five weeks. Comparison of the baseline brushing and no-brushing periods indicated that four times as much plaque accumulated during the no-brushing period as during the brushing period. Use of the antibiotic erythromycin reduced plaque by 35 percent compared to the formation in the nobrushing period. However, the use of the antibiotic alone was not as effective as brushing in reducing the accumulation of plaque. After withdrawal of the antibiotic, the accumulation of plaque was as high as after the no-brushing period, so that the carryover effect, which had been demonstrated in experimental animals, was not seen in humans. In addition, there were no dramatic effects of the drug on streptococci or polysaccharide-forming microorganisms. The only positive effect of the antibiotic was on spirochetes, which were present in all subjects at the outset of the study, but which did not reappear in the oral flora for 18 weeks after the administration of erythromycin. The topical short-term use of broad-spectrum antibiotics to control plaque does not appear to be a practical approach to plaque control when measured against the use of these chemotherapeutic agents to fight life-threatening infections. A more practical approach to the control of plaque would be the use of powerful bacteriocidal or bacteriostatic chemicals which are riot used to treat other infectious
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diseases. The bisbiguanides are a series of compounds which have demonstrated superior antimicrobial properties.32 Alexidine (2 ethylhexyl bisbiguanidine dihydrochloride), which belongs to the same family of chemical compounds as chlorhexidine, has been shown to be highly effective in inhibiting plaque formation and preventing gingivitis in rats and hamsters. The drug is of low oral toxicity and poorly absorbed from the gastrointestinal tract. It is active against pathogenic yeasts, thus virtually eliminating the possibility of the development of moniliasis with continued use. In limited human use, alexidine-resistant strains of microorganisms have not emerged. A group of short-term, no-brushing cross-over clinical trials evaluated mouthwashes containing alexidine in a concentration of 0.035-0.05 percent.33-35 The antimicrobial rinse was used for one minute, either once or twice daily, for a period of two weeks. All studies reported a significant reduction in plaque and gingivitis. Several clinical trials of six months' duration have demonstrated similar findings when alexidine was used as a mouthwash to supplement routine daily oral hygiene procedures.3 6-39 These studies included children and young adults, the groups that would benefit most from the potential for the prevention of oral disease demonstrated with the use of alexidine. In these studies, the beneficial effect on oral health of the chemotherapeutic agents was superimposed upon the benefits already gained from the practice of normal oral hygiene. Side effects have been few except for the occurrence of a transient extrinsic brown stain on the tongue, teeth, and occasionally the oral mucosa. These teeth stains were easily removed by simple prophylaxis. To date, the bisbiguanides have shown the most promising potential for the therapeutic control of dental plaque and the plaquerelated diseases. As indicated previously, the initial step in the formation of plaque on a freshly cleansed tooth surface is the sorption of salivary proteins to enamel. A number of surfactants have been investigated to determine their ability to alter the wettability of enamel and the sorption of proteins, and consequently to affect plaque formation on tooth surfaces.40 Usdin et al.41 immersed
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human enamel in dilute solutions of pyromellitic acid (1, 2, 4, 5, benzenetetracarboxilic acid) and reduced protein sorbtion from whole saliva by 58 percent. This finding prompted the use of pyromellitic acid in a clinical trial because it is relatively nontoxic. Interestingly, when added to cultures of microorganisms, it did not prevent bacterial growth. This might be an advantage in that the beneficial elements of the local environment could be preserved. In a threeday, no-brushing study, plaque accumulation following a prophylaxis was significantly reduced using a pyromellitic acid mouthwash, compared to the results of a placebo treatment.42 In a two-week brushing study in which subjects used a liquid pyromellitic acid dentifrice twice daily, a similar reduction in plaque accumulation was found.43 These studies are encouraging because they have demonstrated a reduction in plaque by altering the interface of the tooth with saliva, rather than temporarily killing oral bacteria which may be harmless or beneficial, as well as those which are pathogenic. Other surface active agents such as cetylpyridinium chloride (CPC) have been available and used in mouthwashes for many years. Clinical trials in humans have demonstrated the beneficial effects of CPC for reducing plaque and gingivitis with and without the practice of toothbrushing.4446 In a study involving 60 subjects, the effect of CPC at concentrations of 1:1000 and 1:2000 on gingivitis plaque, plaque pH and plaque flora were studied over a 21-day period of use.47 Subjects practiced customary toothbrushing and rinsed with 20 ml of CPC for 20 seconds, twice daily, for 21 days. At both concentrations of CPC, gingivitis was significantly reduced by 40 percent. As measured by dry weight, plaque was also reduced for the CPC groups. Microbiological assays for total aerobes, anaerobes and streptococci were significantly reduced as were counts for Streptococcus mutans during the 21 days the drug was used. All bacterial cell counts returned to near normal levels seven days after the CPC rinses were discontinued. Interestingly, CPC users showed more extrinsic stain than the placebo group. More recently, a six-month clinical trial which studied the effect of the daily use of CPC mouthwashes on plaque and gingivitis was completed. In this longer
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term trial, both plaque and gingivitis
scores
significantly reduced in the CPC groups. 48 Other compounds which have demonstrated activity against plaque and gingivitis are the organic amine fluorides.49-51 While these compounds are known to have bacteriostatic activity against plaque, they have also been shown to reduce caries by approximately 35 percent when incorporated into a dentifrice.52 The mechanism of action is postulated to be due to fluoride uptake by hydroxyapatite, blocking of bacterial enzyme systems, and surfactant action which enhances cell uptake of the amine fluorides. These compounds are interesting because of their potential "double barrel" clinical effect in reducing both were
caries and
gingivitis.
Chemicals such as oxidizing and reducing agents, antiseptics, antimicrobials, alkalizers, and bleaching agents have also been investigated for their antiplaque properties. However, they have not been used long enough to determine their true worth for the control or prevention of dental disease. The continual study of these chemotherapeutic agents should be encouraged because many of these drugs have been shown to be safe for human use. These drugs may have been shelved simply because an effective delivery system has not been developed which will localize the drug to a specific site, control its release, and potentiate its action. Another symposium on controlled and sustained release agents in dentistry, held at this meeting, reported several new practical approaches to the delivery of drugs to sites where the tooth, acquired pellicle and gingival epithelium interface. In approaching this problem, Katz and Park53 have proposed a system of "enamel conditioning," which would enhance the incorporation of antiplaque agents into enamel by first treating enamel with a mild chelating agent. The slightly decalcified enamel is then immediately treated with a reprecipitating agent such as stannous fluoride, since it contains an antimicrobial agent which becomes trapped in the reconstituted enamel. They found that enamel treated with compounds like hexachlorophene and fluorophene very effectively resisted in vitro plaque formation. Moreno et al.54 have found in recent studies that the acquired pellicle of enamel in fluoridated areas
differs from that in nonfluoridated areas. Their findings suggest that the cariostatic effect of fluoride may be due to a change in the composition of the pellicle formed in these different areas as well as the incorporation of fluoride into hydroxyapatite. These examples of new approaches to the enhancement of the chemotherapeutic effects of antiplaque agents suggest that now may be the time to go to the shelf and re-evaluate some of our old safe drugs.
Conclusions. Our current knowledge of dental caries and periodontal disease has identified microorganisms which are localized in specific sites on the enamel, in the gingival crevice, and on the root surface. The chemotherapeutic approach to plaque control continues to have great appeal, because it may be possible to treat these specific sites for a short, controlled period of time with drugs that are highly toxic to the microorganisms. Using an appropriately designed delivery system, this method would provide optimum benefits at minimum risks to the patient. If these drugs were capable of being safely self-administered, it would enhance their cost effectiveness. In lieu of a major breakthrough in drug therapy for control or prevention of dental disease, we must rely on the motivation of people to place good oral health high on their list of priorities.5 5 Since this is not readily happening, next to fluoridation of all public water supplies, the most attractive option we have for the prevention of dental disease is continued research in chemotherapeutics for plaque control. REFERENCES 1. GLASS, R.L.: Personal communication, 1975. 2. NEWBRUN, E.: Cariology, Baltimore: Williams and Wilkins, 1978. 3. KEYES, P. H.: The Infectious and Transmissible Nature of Experimental Dental Caries. Findings and Implications, Arch Oral Biol 1:304-320, 1960. 4. LOESCHE, W. J.: Chemotherapy of Dental Plaque Infections, Oral Sci Rev 9:65-107, 1979. 5. SOCRANSKY, S. S.: Microbiology of Periodontal Disease-Present Status and Future Considerations, J Periodontol 48:497-504, 1977. 6. NEWMAN, M. G.; SOCRANSKY, S. S.; SAVITT, E. D.; PROPAS, D. A.; and CRAW-
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FORD, A.: Studies of the Microbiology of Periodontitis, J Periodontol 47:373-379, 1976. NEWMAN, M. G. and SOCRANSKY, S. S.: Predominant Cultivable Microbiota in Periodontosis, J Periodont Res 12:120-128, 1977. AXELSSON, P. and LINDHE, J.: The Effect of a Preventive Program on Dental Plaque, Gingivitis and Caries in School Children. Results after One and Two Years, J Clin Periodontol 1:126-138, 1974. LOE, H.; THEILADE, E.; and JENSEN, S. B.: Experimental Gingivitis in Man, J Periodontol 36:177-187, 1965. SUOMI, J. D.; GREENE, J. C.; VERMILLION, J. R.; DOYLE, J.; CHANG, J. J.; and LEATHERWOOD, E. C.: The Effect of Controlled Oral Hygiene Procedures on the Progression of Periodontal Disease in Adults: Results after Third and Final Year, JPeriodontol 42:152-160, 1971. LIGHTNER, L. M.;O'LEARY, T. J.; DRAKE, R. B.; CRUMP, P. P.; and ALLEN, M. F.: Preventive Periodontic Treatment Procedures: Results over 46 Months, J Periodontol 42: 555-561, 1971. MECKEL, A. H.: The Formation and Properties of Organic Films on Teeth, Arch Oral Biol 10:585-589, 1965. McDOUGALL, W. A.: Studies on Dental Plaque. II. The Histology of Dental Plaque and its Attachment, Australian Dent J 8: 398407, 1963. MANDEL, I. D.: Dental Plaque: Nature, Formation and Effects, J Periodontol 37: 357-367, 1966. RITZ, H. L.: Microbial Population Shift in Developing Human Dental Plaque, Arch Oral Biol 12:1561-1568, 1967. SOCRANSKY, S. S.: Relationship of Bacteria to the Etiology of Periodontal Disease, J Dent Res (Supplement to No. 2) 49:203222, 1970. KRASSE, B.: Human Streptococci and Experimental Caries in Hamsters, Arch Oral Biol 11:429436, 1966. GIBBONS, R. J. and BANGHART, S.: Synthesis of Extracellular Dextran by Cariogenic Bacteria and its Presence in Human Dental Plaque, Arch Oral Biol 12:11-24, 1967. CARLSSON, J. and EGELBERG, J.: Effect of Diet on Early Plaque Formation in Man, Odont Rev 16:112-125, 1965. GIBBONS, R. J. and NYGAARD, M.: Synthesis of Insoluble Dextran and its Significance in the Formation of Gelatinous Deposits by Plaque-forming Streptococci, Archs Oral Biol 13:1249-1262, 1968. GIBBONS, R. J. and KEYES, P. H.: Inhibition of Insoluble Dextran Synthesis, Plaque Formation, and Dental Caries in Hamsters
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