Controlling Biofilm with Evidence-Based Dentifrices
Sebastian G. Ciancio, DDS
As the oral healthcare profession enters into an era where caries prevalence is reduced, many dental clinicians seek integrated approaches to address both caries and gingivitis prevention and management. The latter requires an understanding of oral biofilms, and specifically the role biofilm plays in contributing to both the caries and gingivitis processes. To effectively and efficiently manage these processes, proposed interventions should have proven therapies that can produce both anti-cariogenic and anti-gingivitis effects.
Early-intervention strategies using antibacterial agents, fluorides, sealants, dietary counseling, and self-management tools have all been found to be effective in the prevention of caries and gingivitis. However, an individual’s daily home oral hygiene routine remains a vital component of oral disease prevention. It is in this context that the incorporation of clinically proven, evidence-based dentifrices with additional benefits beyond those traditionally associated with fluoride toothpaste (ie, those with antimicrobial/antibacterial agents that prevent or reduce gingivitis/periodontitis) may be useful. Furthermore, if such dentifrice products are perceived by consumers to have greater value—such as cosmetic tooth-whitening benefits, breath-freshening capabilities, leaving a sense of mouth freshness and cleansing, and disease prevention—consumers will be more likely to purchase and implement those products at home. Although patients can use more than one product to produce the individual benefits listed, compliance data has shown that the more products a patient is told to use, the less they will comply. Therefore, one product with multiple benefits favors compliance.1
An excellent meta-analysis of antiseptic agents for the control of plaque and gingivitis was recently published by Gunsolley.2 He concluded there was insufficient evidence to demonstrate efficacy for other triclosan toothpaste systems containing soluble pyrophosphate or zinc citrate. Therefore, this article will focus on the triclosan/copolymer dentifrice formulation while providing information on two less clinically studied agents, stannous fluoride and zinc.
Triclosan is a broad-spectrum antimicrobial agent that is marketed for use in oral products.3-15 In the early 1990s, the Colgate-Palmolive Company introduced a novel dentifrice called Colgate® Total® Toothpaste. The dentifrice contains 0. 3% triclosan, 2% polyvinylmethyl ether maleic acid (PVM/MA) copolymer, and 0. 243% sodium fluoride in a silica base. The addition of the copolymer to the dentifrice formulation allowed a greater uptake and retention of the triclosan to the enamel and buccal epithelial cells than triclosan alone, providing a long-lasting effect that has been well-documented.16 Daily use of this triclosan/copolymer dentifrice can provide up to 12 hours of antibacterial protection and, as a result, up to 12 hours of plaque biofilm control. In the United States, triclosan as a dentifrice additive is only available in Colgate® Total. Outside the United States, it is found in mouth rinses without the copolymer and in dentifrices.
The clinical efficacy of the triclosan/copolymer dentifrice relative to plaque and gingivitis control was demonstrated in more than 2,000 subjects who participated in thirteen 6-month, independent, double-blind clinical studies using a similar study design.17-29 Results (summarized in Table 1) reported a reduction in plaque for the triclosan/copolymer dentifrice when compared to the placebo dentifrice of up to 58.9% for plaque reduction and up to 41.9% for gingivitis reduction. Studies have also shown significant reductions in supragingival calculus formation ranging from 23% to 57% with an average reduction of 37%.24,25
Effect on Periodontitis
In addition to the anti-plaque and anti-gingivitis effects of the 0.3% triclosan and 2% PVM/MA copolymer fluoride dentifrice, six studies have been conducted to demonstrate the effects of the dentifrice on the post scaling and root planing management of patients with periodontitis. Subjects in these studies completed a course of initial therapy followed by a course of home care/maintenance which included a triclosan/copolymer dentifrice used twice daily during toothbrushing. The rationale for these studies was based on the significant reductions of supragingival plaque biofilm demonstrated for this dentifrice. Because positive changes in supragingival plaque affect the subgingival microflora, it was reasonable to investigate the effect of this dentifrice on the management or progression of periodontitis. These studies are summarized in Table 2. A total of five long-term, randomized, controlled clinical studies in over 1,100 patients have been conducted,23,26-29 ranging from 24 months to 60 months.
Overall, the findings of these studies demonstrated that:
- a dentifrice containing triclosan/copolymer was effective in reducing the progression of disease, the frequency of deep periodontal pockets, and number of sites that exhibited additional probing attachment and bone loss.26
- a dentifrice containing triclosan/copolymer provided a reduction in attachment loss of 50% when compared with a control dentifrice (P < .05) and, therefore, may prevent the onset of the earliest signs of destructive periodontal disease.28
- a dentifrice containing triclosan/copolymer provided a significant periodontal health benefit in those subjects susceptible to periodontal disease.26
- in patients with recurrent disease, clinically significant gains in attachment levels and reduction in pocket depth and bleeding were demonstrated in subjects who used the dentifrice containing triclosan/copolymer.27
Research suggests that the anti-gingivitis and beneficial periodontal effect of the triclosan/copolymer dentifrice result from the combined antimicrobial and anti-inflammatory properties of triclosan. The data from these studies strongly suggest that the triclosan/copolymer/fluoride dentifrice may be the ideal choice for patients on periodic periodontal recall/maintenance visits because of its beneficial effects in maintaining periodontal health and reducing the progression of disease.
Modéer and others 30-35 conducted laboratory studies to assess the anti-inflammatory action of triclosan. These studies demonstrated that triclosan inhibits the production of mediators of inflammation called cytokines. The two major cytokines inhibited by triclosan were interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). The major effect of these cytokines is to stimulate the inflammatory response that often Results in both soft and hard tissue destruction. In addition, IL-1β and TNF-α can induce prostaglandin E2 (PGE2) production, another potent inflammatory mediator, during the early stages of inflammation. PGE2 is a potent stimulator of collagen breakdown and bone resorption, and exhibits a broad range of inflammatory effects. These studies found that triclosan inhibited both IL-1β- and TNF-α-induced PGE2 production for up to 24 hours, most probably due to the inhibition of PGE2 biosynthesis. Finally, recent work indicates that triclosan can inhibit matrix metalloproteinase production in fibroblasts and osteoblasts that were stimulated with inflammatory cytokines.35
Dental professionals should, therefore, consider recommending the twice-daily use of a triclosan/copolymer toothpaste to patients who are susceptible to periodontal disease in the knowledge that it will be a useful adjunct to periodontal preventive and supportive therapies.
The American Dental Association has established guidelines for the conduct of clinical trials to evaluate the effect of oral care products on dental caries.37,38 Four studies on nearly 10,000 subjects were conducted using a triclosan/copolymer/fluoride dentifrice in accordance with ADA guidelines.36,39-41 The overall Conclusion from these four independent double-blind studies is that the triclosan/copolymer/fluoride dentifrice provides an anti-caries benefit that is equal to that provided by conventional fluoride dentifrices.
Oral putrefaction is a biological process which contributes to malodor, as well as plaque and gingivitis. Toothpaste ingredients, especially triclosan, have been shown by virtue of their antibacterial properties to be effective in the treatment of oral malodor. Three clinical studies have demonstrated that a triclosan/copolymer/fluoride dentifrice provides long-lasting fresh breath protection for up to 12 hours after brushing.42-44 In vivo studies show that a dentifrice with triclosan/copolymer has specific activity against volatile sulfur compound (VSC) producing bacteria which may explain the benefits seen on malodor control.45 Since "bad breath" is a concern of most patients, this ADA-accepted efficacy may serve not only the purpose of controlling malodor but also may motivate patients to be more compliant with toothbrushing.
A requirement of the 1986 American Dental Association Guidelines for Acceptance of Chemotherapeutic Products for the Control of Supragingival Dental Plaque and Gingivitis pertains to microbiological monitoring.46 To meet this requirement, four of the long-term plaque and gingivitis clinical efficacy studies3-5,8 included microbiological monitoring of the oral microflora.18-21 All four of these studies confirmed that the use of a dentifrice containing 0.3% triclosan and 2% copolymer over an extended period of time does not result in shifts in the microflora of supragingival plaque favoring the growth of resistant, opportunistic, or pathogenic bacteria species. Also, six subsequent long-term studies specifically designed to evaluate effects on the oral microflora ranging between 6 months and 5 years in duration have confirmed these findings. The lack of adverse effects was not surprising since triclosan has a nearly 4-decade history of safe use in soaps and deodorants.17
Stannous fluoride was first introduced into the US market in the 1950s as a dentifrice ingredient to reduce caries, and its anti-cariogenic effects have been well-established. Later, due to staining and taste issues, it was removed from dentifrices and replaced by sodium fluoride or sodium monofluorophosphate as an anticariogenic agent. Stannous fluoride was reformulated in 1997 into a dentifrice to reduce plaque and gingivitis as well as caries, and addressed the problem of poor stability on exposure to air by introducing a formula which "stabilized" the stannous fluoride. However, it was not successful in the US marketplace possibly because of problems with tooth staining, which has been reported with a number of stannous-fluoride products.47 The antibacterial activity of stannous fluoride is related primarily to the presence of tin (stannous) in the formulation. Binding of the tin to the bacterial surface impedes colonization, and intracellular accumulation of tin affects the metabolic activity of bacteria.The newest formulation reported in this review, Crest® Pro-Health (Procter & Gamble), is a dentifrice containing 0.45% stannous fluoride/sodium hexametaphosphate. Sodium hexametaphosphate has been incorporated into the formulation to aid in the control of calculus and extrinsic tooth staining via inhibition of pellicle formation and mineralization.48,49
Studies of a dentifrice containing stannous fluoride/sodium hexametaphosphate have demonstrated reductions in plaque ranging from 0% to 8. 5% and reductions in gingivitis ranging from 17% to 26%.49-51 These studies are summarized in Table 3. Although tooth staining is common with stannous-fluoride products, it was not reported in the most recent studies on Crest Pro Health. Also, two studies showed that a stannous-fluoride dentifrice did prevent and inhibit the formation of calculus and, in one study, the inhibition was 56% better than that obtained by a triclosan/co-polymer/fluoride dentifrice used in the study.52
It has been demonstrated that when stannous fluoride is supplemented by sodium hexametaphosphate, the formulation has a beneficial effect of controlling stain deposition on the tooth surface.53 Use in patients after periodontal therapy has been studied and data suggests that this agent reduced gingivitis better than sodium fluoride.49-51,54 It has also been shown that stannous fluoride is of benefit in the reduction of dentin hypersensitivity.55 Aside from tooth staining due to stannous fluoride without sodium hexametaphosphate reported in some studies, no serious adverse events have been reported.54
Salts of heavy metals have long been recognized as effective antibacterial agents. Silver nitrate, bichloride of mercury, and zinc chloride were among the agents tested over the years. Because of tooth staining as well as soft tissue and systemic effects, silver and mercury have limited oral use, but zinc has persisted over the years in a variety of oral products.56 Zinc citrate or zinc chloride can have an antibacterial impact by binding to the surface of oral bacteria and affecting bacterial adherence, altering bacterial metabolic activity and reducing bacterial growth rates.
Some studies support the role of zinc in reducing plaque growth.57,58 At appropriate concentrations, zinc-containing agents have anti-calculus properties but taste-acceptance limits the concentrations that can be used.56 In one study that examined the efficacy of zinc compared to chlorhexidine,59 researchers found that there was a reduction of gingivitis, and there was also less stain. One study of zinc looked exclusively at calculus formation, and found a reduction of calculus of greater than 50%.60 In patients on periodontal recall, a zinc-containing dentifrice was found to have a modest benefit in terms of inflammation and plaque reduction in one study.58 A reduction in gingivitis of approximately 20% was reported. There is only one long-term (6 months) study of a zinc-containing compound and it is summarized in Table 4.57 More clinical trials with existing or new formulations containing zinc that document significant reduction of gingivitis are needed before any recommendation of a zinc-containing product can be considered. However, zinc-containing dentifrices have the potential to be of significant benefit in the control of plaque and gingivitis, and further studies are encouraged.
This review summarizes research that has assessed the effectiveness of various antimicrobial-containing dentifrices in preventing and/or reducing a number of oral health problems facing our patients today. The results of these studies indicate that, when compared with a conventional fluoride dentifrice, the triclosan/copolymer/fluoride dentifrice is the one with the most evidence to support its ability to deliver significant oral health benefits with no adverse effects. The benefits may be summarized as follows:
- improved levels of supragingival plaque control;
- improved gingival health;
- reduced likelihood of gingivitis progressing to periodontitis;
- arrest progression of periodontitis;
- prevention of supragingival calculus; and
- reduction in oral malodor.
With increased interest in the association of oral health with systemic health, this dentifrice is well-positioned to help reduce the likelihood of gingivitis establishing itself and possibly developing into periodontitis. It also has the potential to have beneficial effects on general health because of its anti-inflammatory properties. Based on the results presented in this article, it is clear that the general population can derive significant clinical benefits from the daily use of a triclosan/copolymer/fluoride dentifrice. The dental profession should feel confident to recommend its use to patients to improve oral health and maintain or promote overall health.
The author has received grant/research support and honoraria from, and is a current consultant for Colgate Palmolive.
About the Author
Sebastian G. Ciancio, DDS
Distinguished Service Professor and Chairman
Department of Periodontics and Endodontics
Director of the Center for Dental Studies
Clinical Professor, Department of Pharmacology
University of Buffalo State
University of New York (SUNY) at Buffalo
Buffalo, New York
1. Fischman SL, Kugel G, Truelove RB, et al. The motivational benefits of a dentifrice containing baking soda and hydrogen peroxide. J Clin Dent. 1992;3(3):88-92.
2. Gunsolley JC. A meta-analysis of six-month studies of antiplaque and antigingivitis agents. J Am Dent Assoc. 2006;137:1649-1657.
3. Mankodi S, Walker C, Conforti N, et al. Clinical effect of a triclosan-containing dentifrice on plaque and gingivitis: a six-month study. Clin Prev Dent. 1992;14:4-10.
4. Bolden TE, Zambon JJ, Sowinski J, et al. The clinical effect of a dentifrice containing triclosan and a copolymer in a sodium fluoride/silica base on plaque formation and gingivitis: a six-month clinical study. J Clin Dent. 1992;4:125-131.
5. Garcia-Godoy F, Garcia-Godoy F, DeVizio W, et al. Effect of a triclosan/copolymer/fluoride dentifrice on plaque formation and gingivitis: a 7-month clinical study. Am J Dent. 1990;3:515-526.
6. Cubells AB, Dalmau L, Petrone ME, et al. The effect of a triclosan/copolymer/fluoride dentifrice on plaque formation and gingivitis: a six-month study. J Clin Dent. 1991;2:63-69.
7. Deasy MJ, Singh SM, Rustogi KN, et al. Effect of a dentifrice containing triclosan and a copolymer on plaque formation and gingivitis. Clin Prev Dent. 1991;13:12-19.
8. Denepitiya JL, Fine D, Singh MS, et al. Effect upon plaque formation and gingivitis of a triclosan/copolymer/fluoride dentifrice: a 6-month clinical study. Am J Dent. 1992;5:307-331.
9. Palomo F, Wantland L, Sanchez A, et al. Plaque/gingivitis efficacy of triclosan dentifrices. J Dent Res. 1993;72:334.
10. Triratana T, Tuongratanaphan S, Rustogi KN, Volpe AR. The effect on established plaque formation and gingivitis of a triclosan/copolymer/fluoride dentifrice: A six-month clinical study. J Dent Assoc Thai. 1993;43:19-28.
11. Lindhe J, Rosling B, Socransky SS, Volpe AR. The effect of a triclosan containing dentifrice on established plaque and gingivitis. J Clin Periodontol. 1993;5:327-328.
12. Renvert S, Birkhed D. Comparison between 3 triclosan dentifrices on plaque, gingivitis, and salivary microflora. J Clin Periodontol. 1995;22:63-70.
13. Svatun B, Saxton CA, Huntington E, Cummins D. The effects of three silica dentifrices containing triclosan on supragingival plaque and calculus formation and on gingivitis. Int Dent J. 1993;43:441-452.
14. Hu D, Zhang J, Zhang YP, et al. Efficacy of a triclosan/copolymer dentifrice in the control of plaque and gingivitis: A six month study in China. West China Journal of Stomatology. 1997;11:15:335.
15. Allen D, Battista GW, Petrone DM, et al. The clinical efficacy of Colgate Total plus Whitening Toothpaste containing a special grade of silica and Colgate Total Fresh Stripe in the control of plaque and gingivitis: A six-month clinical study. J Clin Dent. 2002;13 (Spec Iss):59-64.
16. Gaffar A, Nabi N, Kashaba B, et al. Antiplaque effects of dentifrices containing triclosan/copolymer/NaF system versus triclosan dentifrices without the copolymer. Am J Dent. 1990;3:S7-S14.
17. Regos J, Zak O, Solf R, et al. Antimicrobial spectrum of triclosan, a broad-spectrum antimicrobial agent for topical application. II. Comparison with other antimicrobial agents. Dermatologica. 1979;158:72-79.
18. Zambon JJ, Reynolds HS, Dunford RG, Bonta CY. Effect of a triclosan/copolymer/fluoride dentifrice on the oral microflora. Am J Dent. 1990;3:S27-S34.
19. Bonta CY, Reynolds HS, Dunford RG, Zambon JJ. Long term effect of a triclosan/copolymer dentifrice on oral microflora. J Dent Res. 1992;71:577.
20. Walker C, Borden LC, Zambon JJ, et al. The effects of a 0.3% triclosan-containing dentifrice on the microbial composition of supragingival plaque. J Clin Periodontol. 1994;21:334-341.
21. Zambon JJ, Reynolds HS, Dunford RG, et al. Microbial alterations in supragingival dental plaque in response to a triclosan-containing dentifrice. Oral Microbiol Immunol. 1994;10:247-255.
22. Fine DH, Furgang D, Bonta Y, et al. Efficacy of a triclosan/NaF dentifrice in the control of plaque and gingivitis and concurrent oral microflora monitoring. Am J Dent. 1998;11:259-270.
23. Cullinan MP, Westerman B, Hamlet SM, et al. The effect of as triclosan-containing dentifrice on the progression of periodontal disease in an adult population. J Clin Periodontol. 2003;30:414-419.
24. Banoczy J, Sari K, Schiff T, et al. Anticalculus efficacy of three dentifrices. Am J Dent. 1995;8(4):205-208.
25. Lobene RR, Battista GW, Petrone DM, et al. Clinical efficacy of an anticalculus fluoride dentifrice containing triclosan and a copolymer: A 6-month study. Am J Dent. 1991;4(2):83-85.
26. Rosling B, Wannfors B, Volpe AR, et al. The use of a triclosan/copolymer dentifrice may retard the progression of periodontitis. J Clin Periodontol. 1997;24:873-880.
27. Furuichi Y, Rosling B, Volpe AR, Lindhe J. the effect of a triclosan/copolymer dentifrice on healing after non-surgical treatment of recurrent periodontitis. J Clin Periodontol. 1999;26:63-66.
28. Ellwood RP, Worthington HV, Blinkhorn AS, et al. Effect of a triclosan/copolymer dentifrice on the incidence of periodontal attachment loss in adolescents. J Clin Periodontol. 1998;25:363-367.
29. Kerdvongbundit V, Wikesjo UM. Effect of triclosan on healing following nonsurgical periodontal therapy in smokers. J Clin Periodontol. 2003;30:1024-1030.
30. Modéer T, Bengtsson A, Rolla F. Triclosan reduces prostaglandin biosynthesis in human gingival fibroblasts challenged with interleukin-1 in vitro. J Clin Periodotol.1996;23:927-933.
31. Sköld-Larsson K, Yucel-Lindberg T, Twetman S, Modéer T. Effect of a triclosan-containing dental gel on the levels of prostaglandin I2 and interleukin-1beta in gingival crevicular fluid from adolescents with fixed orthodontic appliances. Acta Odontol Scand. 2003;61(4):193-196.
32. Mustafa M, Wondimu B, Ibrahim M, Modéer T. Effect of triclosan on interleukin-1β production in human gingival fibroblasts challenged with tumor necrosis factor α. Eur J Oral Sci. 1998;106:637-643.
33. Mustafa M, Bakhiet M, Wondimu B, Modéer T. Effect of triclosan on interferon-[gamma] production and major histocompatibility complex class II expression in human gingival fibroblasts. J Clin Periodontol. 1998;27(10):733-737.
34. Mustafa M, Wondimu B, Yucel Lindberg T, et al. Triclosan reduces microsomal prostaglandin E sythase-1 expression in human gingival fibroblasts. J Clin Periodontol. 2005;32:6-11.
35. Panagakos FS, Kumar E. Triclosan inhibition of cytokine-stimulated MMP production by osteoblast-like cells. J Dent Res. 2003;82:2248.
36. Feller R, Kiger R, Triol C, et al. Comparison of the clinical anticaries efficacy of an 1100 NaF silica based dentifrice containing triclosan and a copolymer to an 1100 NaF silica based dentifrice without those additional agents: a study on adults in California. J Clin Dent. 1996;7:85-89.
37. Council on Dental Therapeutics. Report of a workshop aimed at defining guidelines for caries clinical trials: superiority and equivalence claims for anticaries dentifrices. J Am Dent Assoc .1988;117:663-665.
38. Proskin HM, Kingman A, Naleway C, Wozniak WT. Comparative attributes for the description of the relative efficacy of therapeutic agents: general concepts and definitions, and application to the American Dental Association Guidelines for the comparison of the clinical anticaries efficacy of fluoride dentifrices. J Clin Dent. 1995;6:176-184.
39. Hawley GM, Hamilton FA, Worthington HV, et al. A 30-month study investigating the effect of adding triclosan/copolymer to a fluoride dentifrice. Caries Res. 1995:29:163-167.
40. Mann J, Kamiel C, Triol C, et al. Comparison of the clinical anticaries efficacy of a 1500 NaF silica based dentifrice containing triclosan and a copolymer to a 1500 NaF silica based dentifrice without those additional agents: a study on adults in Israel. J Clin Dent. 1996;7:90-95.
41. Mann J, Vered Y, Babayof I, et al. The comparative anticaries efficacy of a dentifrice containing 0.3% triclosan and 2.0% copolymer in a 0. 243% sodium fluoride silica base. J Clin Dent. 2001;12:71-76.
42. Sharma N, Galustians HJ, Qaquish J, et al. The clinical effectiveness of a dentifrice containing triclosan and a copolymer for controlling breath odor measured organoleptically twelve hours after toothbrushing. J Clin Dent. 1999;4:131-134.
43. Niles HP, Vazquez J, Rustogi KN, et al. The clinical effectiveness of a dentifrice containing triclosan and a copolymer for providing long term control of breath odor measured chromatographically. J Clin Dent. 1999;4:135-138.
44. Sharma NC, Galustains HJ, Qaqish J, et al. The clinical efficacy of Colgate total plus whitening toothpaste containing a special grade of silica and Colgate total toothpaste for controlling breath odor twelve hours after toothbrushing. A single-use clinical study. J Clin Dent. 2002;13(Spec Iss):73-76.
45. Sreenivasan PK, Furgang D, Zhang Y, et al. Antimicrobial effects of a new therapeutic liquid dentifrice formulation on oral bacteria including odorigenic species. Clin Oral Investig. 2005;9(1):38-45.
46. Guidelines for Acceptance of Chemotherapeutic Products for the Control of Supragingival Dental Plaque and Gingivitis, American Dental Association Council on Dental Therapeutics. J Am Dent Assoc. 1986;112:529-532.
47. White DJ. A new and improved "dual action" whitening dentifrice technology—sodium hexametaphosphate. J Clin Dent. 2002;13:1-5.
48. White DJ, Cox ER, Suszcynskymeister EM, Baig AA. In vitro studies of the anticalculus efficacy of a sodium hexametaphosphate whitening dentifrice. J Clin Dent. 2002;13:33-37.
49. Archilla L, Bartizek RD, Winston JL, et al. The comparative efficacy of stabilized stannous fluoride/sodium hexametaphosphate dentifrice and sodium fluoride/triclosan/copolymer dentifrice for the control of gingivitis: a 6-month randomized clinical study. J Perio. 2004;75:1592-1599.
50. Mankodi S, Bartizek RD, Winston JL, et al. Anti-gingivitis efficacy of a stabilized 0.4 54% stannous fluoride/sodium hexametaphosphate dentifrice. A controlled 6-month clinical trial. J Clin Periodontol. 2005;32:75-80.
51. Mallatt M, Mankodi S, Bauroth K, et al. A controlled 6-month clinical trial to study the effects of a stannous fluoride dentifrice on gingivitis. J Clin Periodontol. 2007;34:762-767.
52. Schiff T, Saletta L, Baker RA, et al. Anticalculus efficacy and safety of a stabilized stannous fluoride/sodium hexametaphosphate dentifrice. Compend Contin Educ Dent. 2005;26(9 Suppl 1):29-34.
53. Mankodi S, Lopez M, Smith I, et al. Comparison of two dentifrices with respect to efficacy for the control of plaque and gingivitis, and with respect to extrinsic tooth staining: a six-month clinical study on adults. J Clin Dent. 2002;13(6):228-233.
54. Boyd RL, Leggott PJ, Roberson PB. Effects on gingivitis of two different 0. 4% SnF2 gels. J Dent Res. 1988;67(2):503-507.
55. Schiff T, Saletta L, Baker RA, et al. Desensitizing effect of a stabilized stannous fluoride/sodium hexametaphosphate dentifrice. Compend Contin Educ Dent. 2005;26(9)(Suppl 1):35-40.
56. Lobene RR, Soparkar PM, Newman MB, Kohut BE. Reduced formation of supragingival calculus with use of fluoride-zinc chloride dentifrice. J Am Dent Assoc. 1987;114:350-352.
57. Williams C, McBride S, Mostler K, et al. Efficacy of a dentifrice containing zinc citrate for the control of plaque and gingivitis: a 6-month clinical study in adults. Compend Contin Educ Dent. 1998:19(2 Suppl):4-15.
58. Günbay S, Biçakçi N, Güeri T, Kirilmaz L. The effect of zinc chloride dentifrices on plaque growth and oral zinc levels. Quintessence Int. 1992;23(9):619-624.
59. Sanz M, Vollcorba N, Fabregues S, et al. The effect of a dentifrice containing Chlorhexidine and zinc on plaque, gingivitis, calculus and tooth staining. J Clin Periodontal. 1994;21(6):431-437.
60. Sowinski J, Petrone DM, Battista G, et al. Clinical efficacy of a dentifrice containing zinc citrate: a 12-week calculus clinical study in adults. Compend Contin Educ Dent. 1998;19(2 Suppl): 16-19.