Chemical plaque control GUIDED BY Dr.V.R.Balaji MDS 1 1 G.Kalaivani 3 rd yr pg
2 content Introduction Concept of chemical plaque control History Rationale of Antiplaque agents Approaches to Antiplaque agents Methods to evaluate Antiplaque agents Ideal properties of Antiplaque agents Groups of agents used in antiplaque agents Recent advances Future trends Conclusions References
3 INTRODUCTION: Chemical plaque control definitive edge over mechanical plaque control, in that access to the areas beyond the preview of mechanical plaque control therapy provides an effective plaque control.
4 Concept of chemical plaque control
5 plaque
6
7 history
8 The terminology “ oral hygiene products ” is recent 6000 years, that formulation and recipes existed to benefit oral and dental health (Fischman 1997). Ebers Papyrus 1500 BC - recipes for tooth powders and mouth rinses Alcohol-based mouth rinses -the Romans and included white wine and beer. Urine, as a mouth rinse Use of stale urine- Cantabri and others in Spain Use of fresh urine-Fauchard (1670-1761) of France.
9 19 th centuries : Use of essential oils in the form of mouth rinse, later with addition of antimicrobial or antiseptics agents to the tooth paste and mouth rinse developed.
10 RATIONALE FOR CHEMICAL PLAQUE CONTROL:
11 prevent gingivitis periodontitis
12 The concept of chemical plaque control may be justified overcoming inadequacies of mechanical cleaning .
13 APPROACHES TO CHEMICAL PLAQUE CONTROL:
14 Mechanical cleaning aims to regularly remove sufficient microorganisms to leave a “healthy plaque” present, which cannot induce gingival inflammation. Chemical agents, on the other hand, could influence plaque control quantitatively and qualitatively. .
15 The action of the chemicals could fit into four categories: 1. Antiadhesive 2. Antimicrobial 3. Plaque removal 4. Antipathogenic.
16 Antiadhesive act at the pellicle surface to prevent the initial attachment of the primary plaque-forming bacteria. prevent the attachment and development of a variety of biofilms and are usually described as antifouling agents. Prevention of extrinsic stain. Toxic Not under research
17 Antimicrobial inhibition of bacterial attachment and bacterial proliferation/division.
18 Plaque removal act in an identical manner to a toothbrush and remove bacteria from the tooth surface, is an attractive proposition. “the chemical toothbrush ”. Contained in mouthrinse,dentifices etc Very effective
19 Antipathogenic. agent could have an effect on plaque microorganisms, which might inhibit the expression of their pathogencity without necessarily destroying the microorganisms- Cummins 1992 I.e. alter the pathogeniticity of plaque.
20 How to proove ? METHODS IN VITRO OR IN VIVO TO EVALUATE ORAL HYGIENE PRODUCTS:
21 ANTIMICROBIAL TESTS : measures of minimum inhibitory concentration and kill curves using bacterial strains or fresh isolates Factors considered: Unless the active age nt has a peculiar profile for certain bacteria, the detergent effect may hide the activity of the active ingredient. Substantivity appears to be a crucial property of effective antimicrobial antiplaque agents.
22 Other in vitro tests: Stain removal, detrimental actions, such as abrasivity . Probably as a function of pH some types of mouth rinse and toothpaste have the potential to erode tooth tissue- Addy et al. Stain control is perhaps more easily modeled, particularly using forced staining methods involving chlorhexidine - Addy et al in 1991 evidence
23 In vivo method: Parallel, randomized control method to be done
24 Clinical significance can be assessed as follows: Benchmark efficacy : - effect similar to other established products; Positive efficacy : -effect similar to or greater than the most effective formulation to date; Disease efficacy : effect on a causative factor that reduces a disease or condition; Proportional efficacy : achieving a previously agreed proportional reduction in a parameter compared with control.
25 A major feature of scientific research, particularly in clinical trials, is the use of controls Placebo control : one without any expected activity against the condition under investigation; Minus active ingredient control : one that is identical to the test product or formulation without the active agent or agents; Benchmark control : a product already in use by the public or an agent already evaluated; and Positive control : an accepted effective formulation or the most effective formulation available to date
26 Among plaque control agents, chlorhexidine has tended to be considered a positive control or gold standard by which to compare other chemicals- Addy et al and Kornman 1986.
27
28 CRITERIA FOR USAGE OF ANTIMICROBIALS: Substantivity : The ability of an agent to be bound to the pellicle and tooth surface and to be released over an extended period of time with the retention of its potency. Stability : chemical breakdown or modification may occur during storage, especially at elevated temperatures. Penetrability : For a drug to be effective, it must be able to penetrate deep into the formed plaque matrix. Toxic safety : any agent used for prevention or treatment of oral diseases must have low toxicity .
29 AGENTS FOR CHEMICAL PLAQUE CONTROL Kornman, 1986; Mandel, 1988
30
31 ANTISEPTIC AGENT: Newbrun 1985
32 DEPENDING ON THE ANTIMICROBIAL EFFICIENCY AND RELATIVE SUBSTANTITIVITY. Generation of anti-plaque agents: Kornman 1986
33
34 FIRST GENERATION AGENTS: 1 st generation: decreases plaque scores by 20-50%, but efficacy is decreased by poor retention in the mouth. E.g. antibiotics, phenols etc.
PHENOLS AND ESSENTIAL OIL : plaque inhibitory anti-inflammatory action anti oxidative activity ( Firalti et al al 1994) exert non specific antibacterial action dependent upon ability of drug to penetrate lipid component of cell walls of gram negative bacteria inhibit neutrophil chemotaxis, generation of neutrophil superoxide ion and production of prostaglandin synthetase- Charles et al 2004.
36 Positive facts
37 TRICLOSAN Phenol derivative –employed by Lister in 1867 (Eley 1998) Is synthetic and ionic Used as a topical antimicrobial agent Broad spectrum of action including both gram positive and gram negative bacteria It also includes mycobacterium spores and Candida species .
38 Mechanism of action: Triclosan Act on cytoplasmic membrane Induce leakage of cellular constitutes Bacteriolysis and cell death
39 AVAILABILITY
40 Ciancio et al demonstrated the value of twice-daily use in the maintenance of dental implants compared with a control mouth rinse. Ciancio has further reported that use of an essential oil mouthwash as a subgingival irrigation prior to scaling greatly reduced anaerobic and aerobic bacterial populations associated with bacteremia and that pre-procedural rinsing The favorable results for a mouth rinse containing phenolic essential oils at inhibiting plaque and reducing gingival inflammation have more recently led to its evaluation for use as a post-surgical rinse- Laspia et al
41 . Zinc salts: plaque inhibitor was first described by Hanke in 1940 Astringent Zinc citrate has been combined with ionic antimicrobial triclosan in toothpaste form, significant anticalculus activity. Zinc salts may be of value at reducing volatile sulfur compounds associated with oral malodor ( Rosing et al 2002). METALLIC IONS
42 Tin salts : • Inhibit plaque formation Svatun et al 1977 showed mechanism of action of tin is through their ability to bind to teichoic acid present on cell wall of gram positive organisms changing surface charge causing decreased adsorption of cells to teeth.
43 Disadvantage of metal salts: Metallic taste Dryness of mouth Yellowish brown discoloration of teeth and tongue Stannous fluoride mouth rinses: Difficult to formulate – stability problems – hydrolysis in presence of water anhydrous gel & toothpaste (Beiswanger et al 1995, Perlich et al 1995) Human studies confirmed that antibacterial action of stannous fluoride was more due to tin ions although they have synergistic effect (Andreas et al 1974).
44 3. QUARTERNARY AMMONIUM COMPOUNDS Cationic antiseptics & surface active agents Effective against gram positive organisms Mechanism of action Positively charged molecule reacts with negatively charged cell membrane phosphates and thereby disrupts the bacterial cell wall structure E.g.: Benzanthonium chloride, Benzalleonium chloride and cetylpyridinium chloride.
45 CETYLPYRIDINIUMCHLORIDE (CPC): used as agents for plaque inhibition cationic CPC at 0.05% conc used in wide variety of antiseptic mouth rinse products. Substantivity of cetylpyridinium chloride is only 3– 5 hours (Roberts & Addy 1981 ). Efficacy of CPC – increased by doubling frequency of rinsing to 4 times per day (Bonsvoll & Gjermo 1978) – increased side effects & affect compliance
46 Side effects: Brownish discoloration of teeth Recurrent apthous type ulceration of oral mucosa. Mouth rinses combining CPC with CHX – studies done – compare well with CHX (Quirynen et al 2001, 2005) – cannot be assessed – whether CPC actually contributes to activity of chx Slow release system & lozenges to deliver cps – no greater plaque inhibition than CPC rinse & significantly < chx rinse (Vanderkerchove et al 1995).
47 Natural products
48 SANGUINARINE: benzophenanthredine alkaloid derived from Sanguinaria Canadensis. It is most effective against gram –ve organisms Properties: Used in mouth rinse Adverse effects: Mouth rinses shown to increase likelihood of oral precancerous lesions ten-fold even after cessation of use
49 Topically delivered tea tree oil - suggested to be of value in reducing gingival inflammation (Sookoulis & Hirsch 2004).
50 PROPOLIS natural resinous material produced by honey bees More than 300 components have been found in propolis , mainly composed of phenolic compounds (e.g., flavonoids, aromatic compounds), terpenes , and essential oil. Flavonoids and cinnamic acid. antimicrobial properties, the use of it as a mouthwash is questionable- Murray et al 1997.
51 LIPPIA SIDOIDES mouthwash northeast of Brazil. as a topical antiseptic agent for skin and mucosa surface and also for throat infections. essential oil - thymol and carvacrol and other substances, such as felandreno , cariofileno , p- cimeno , and mirceno . Studies indicated that these major components had shown potent antimicrobial activity against fungi and bacteria and reduced the severity of gingivitis and bacterial plaque- Rodrigues IS et al.
52 ALOE VERA EXTRACT Aloe vera gel consists of 98 to 99% water and the remaining 1 to 2% of active compounds. aloin, aloeemodin, aloemannan, acemannan, aloeride , naftoquinones, methylchromones, flavonoids, saponin, sterols, amino acids, and vitamins. A randomized controlled study using 100% aloe vera extract showed significant reduction in plaque formation with no reported side effects. The antimicrobial effect of aloe vera has been demonstrated earlier in an in vitro study.
53 Antibiotics
54 Due to bacterial resistance problems the use of antibiotics has been reduced. Despite evidence for efficacy – systemic antimicrobials used in past (as topical/ systemic) are Penicillin, Vancomycin, Erythromycin) for preventing caries & gingivitis. Not be used as preventive agents. Risk-to-benefit ratio is high (Slots & Rams 1990; Addy & Martin 2003).
55 SECOND GENERATION AGENTS: • More effectively retained by oral tissues and slow release properties provide reduction in plaque scores between 70 and 90% • E.g.: Bisbiguanides.
56 BISBIGUANIDES Considered to most effective antiplaque agents. Second generation agents exhibiting substantivity broad antimicrobial properties.
57 CHLORHEXIDINE the gold standard. Developed in 1940s by Imperial Chemical Industries England - marketed in 1954 – as antiseptic for skin wounds. Available in 3 forms: digluconate, acetate & hydrochloride salts
58 Structure: Symmetrical molecule • Four chlorophenyl rings & two biguanide groups connected by central hexamethylene bridge. • Compound is strong base & dicationic > pH 3.5, with two positive charges on either side of hexamethylene bridge .
60 Antimicrobial Bacteriostatic At low concentration Bacteriocidal At high concentration Bacterial cell wall (-ve charge) Reacts with +ve charged chlorhexidine molecule CHX binds to inner membrane phospholipids & increase permeability Vital elements leak out & this effect is reversible
62 ANTI PLAQUE ACTION :
63 CHX due to its dicationic nature binds to enamel pellicle or tooth surface and salivary proteins. This adsorbed CHX is released of a period of time. Substantivity Binds different surfaces within the mouth (teeth and mucosa) and also to the pellicle and saliva; for example, after a single rinse with chlorhexidine , the saliva itself exhibits antibacterial activity for up to 5 hours, whereas persistence at the oral surfaces has been shown to suppress salivary bacterial counts for over 12 hours
64 Metabolism: • Does not penetrate oral epithelium (Lindhe et al 1970). • If accidentally swallowed – bind to mucosal surface of alimentary canal - is poorly absorbed & all of swallowed dose excreted in feces.
65 Oral retention of chlorhexidine: clinical data Efficacy with respect to other drugs. persistent bacteriostatic action lasting > 12 hours ( Schiott et al 1970) When mouth rinse of 10 ml of 0.2% chlorhexidine is done for 1 min app- 30% drug is retained in mouth ( Gjermo 1975). Reasons: Radio-labeled studies suggest slow release of antiseptic from surfaces ( Bonesvoll et al. 1974) ( Gjermo et al. 1974) Calcium ions from saliva are able to displace it from binding sites
66 Optimizing use of chlorhexidine: Does not distinguish between bacterial protein & other proteins found within mature plaque so extraneous protein must first be removed professionally. Prevents plaque formation; its mode of action does not allow it to remove plaque efficiently. May react with anionic surfactants present in formulations reducing its activity. Should not be used before/ immediately after toothpaste; interaction anionic surfactants will reduce effective delivery to tooth surface in active form
67 ADVERSE EFFECTS OF CHLORHEXIDINE:- Flotra et al. 1971 Brown discoloration of teeth & some restorative materials & dorsum of tongue. Occurs with all products – rinse, gel, toothpastes, sprays (Erikson et al 1985, Addy & Moran 1995, Watts & Addy 2001)
68 Proposed mechanisms for chlorhexidine staining : Degradation of CHX molecule to release parachloraniline. Catalysis of Maillard reactions. Protein denaturation with metal sulfide formation. Precipitation of anionic dietary chromogens splitting sulphide bridges to produce free sulpydryl groups , latter then reacts with iron or tin ions to produce brown and yellow pigmented products (Ellingsten et al 1882) Chlorhexidine reacts with ketones and aldehydes in dietary breakdown or intermediary products to form insoluble colored compounds ( Nordho 1971)
69 Anti-discoloration system (ADS ) was launched=Europe A clinical study supporting to show reduced staining had significant drawbacks in design and presentation (Bernadi et al. 2004 ). A laboratory study found no difference in staining potential (Addy et al. 2005 ).
70 Plaque regrowth study showed significantly reduced plaque inhibition for the ADS rinse (Arweiler et al. 2006). “If it does not stain it does not work”.
71 Taste perturbation where salt taste appears to be affected (Lang et al. 1988 ).
72 Oral mucosal erosion - idiosyncratic reaction and concentration dependent. Dilution of 0.2% formulation to 0.1%, but rinsing with whole volume to maintain dose, usually alleviates problem. Erosions are rarely seen with 0.12% rinse products used at 15 ml volume. ISP 2012
73 Unilateral or bilateral parotid swelling extremely rare - negative pressure & aspiration into duct.
74 Enhanced supragingival calculus formation – may be due to precipitation of salivary proteins on to tooth surface – increasing pellicle thickness &/or precipitation of inorganic salts on to or into pellicle layer
75 CHLORHEXIDINE PRODUCTS Mode of delivery of CHX: mouth rinse, gels, tooth paste, dental floss, and tooth picks.
76 Mouth rinses: • Aqueous solutions of 0.2 % chlorhexidine – twice daily rinse in Europe in 1970s • 0.1% - less efficacious (Jenkins et al 1989). • In US - 0.12% - but to maintain optimum 20 mg doses derived from 10 ml of 0.2% rinses - recommended as 15 ml rinse (18 mg dose). • Segreto et al 1986 reported equal efficacy for 0.2% & 0.12 % rinses when used at appropriate similar doses 0.2% 0.12% 0.05%
77 Gel • 1% chlorhexidine gel product is available and can be delivered on a toothbrush or in trays. • Distribution by toothbrush – poor (Saxen et al 1976) • Tray delivery system - effective against plaque & gingivitis in handicapped individuals (Francis et al. 1987). • 0.2% and 0.12% chlorhexidine gels have become available
78 Sprays: • 0.1% & 0.2% commercially available. • Small doses of approximately 1–2 mg delivered to all tooth surfaces produces similar plaque inhibition to rinse with 0.2% mouth rinses ( Kalaga et al. 1989) • Useful for physically and mentally handicapped groups-Francis et al 1987, Kalaga et al 1989).
79 Toothpaste: • Yates et al 1993 • Difficult to formulate into toothpaste • Variable outcomes for benefits to plaque & gingivitis • 1% chlorhexidine toothpaste with & without fluoride – found superior to control product for prevention of plaque and gingivitis in a 6-month home use study • Stain scores were increased supragingival calculus formation
varnish
81 CLINICAL USES • Adjunct to oral hygiene & professional prophylaxis • Post oral surgery including periodontal surgery or root planing • For patients with jaw fixation • Oral hygiene and gingival health benefits in mentally & physically handicapped • Medically compromised individuals predisposed to oral infections Removable and fixed orthodontic appliance Recurrent oral ulcers Denture stomatitis Oral malodor High-risk caries patients
82 PERIOCHIP ( D excel Pharmaceuticals, Israel) orange brown, biodegradable, rectangular chip rounded at one end that has an active ingredient of chlorhexidine gluconate (2.5 mg) that is released into the pocket over a period of 7 to 10 days. suppress the pocket flora for up to 10- 11 weeks post application. approved by the FDA as an adjunct to SRP procedures for the reduction of probing pocket depth or as part of a routine periodontal maintenance program.
83 The recommendation for use adjunctive to SRP involves isolation of the periodontal pocket of 5 mm or more. Drying the surrounding area, and grasping the Periochip with a forceps and inserting the chip into the pocket to its maximum depth The chip can be maneuvered further into position with a plastic instrument .
84 THIRD GENERATION AGENTS (Addy et al 2007) • Characterized by an ability to inhibit or disrupt formation of plaque while having no demonstrable effect on bacteria E.g.: amine alcohols
85 AMINE ALCOHOLS do not truly fit into antimicrobial/ antiseptic category • Low surface tension and lipophillic, hydrophilic property can affect plaque growth without affecting ecological balance Octopinol - first to be shown effective as antiplaque agent – withdrawn for toxicological reasons Delmopinol at 0.1% & 0.2% mouth rinses – shown to be effective against plaque & gingivitis in short term long term home use studies. ( Collaert et al 1992, Claydon et al 1996, Hase et al 1998, Lang et al 1998)
86 Side effects: Tooth discoloration - less and easily removed Transient numbness of tongue Burning sensations in mouth ( Claydon et al 1996, Hase et al 1998, Lang et al 1998) Positive facts • Effectiveness of delmopinol, coupled with its qualitatively and quantitatively greatly reduced potential for tooth staining compared with chlorhexidine (Lang et al. 1998) makes this compound potentially an attractive alternative to chlorhexidine for plaque control.
87 OTHERS: SALIFLUOR : A salicylanide with both antibacterial and anti-inflammatory properties. • Studied for its effects of plaque inhibition and retardation of onset of gingivitis ( Furuichi et al. 1996 ). • Initial 4 day plaque regrowth studies & 14- day gingivitis studies have suggested equivalent efficacy to 0.12% chlorhexidine mouth rinse ( Furuichi et al. 1996 ) • Despite this – long term studies yet to be carried out
88 ACIDIFIED SODIUM CHLORITE • Yates et al 1997 • Sodium chlorite is reacted with acid to produce chlorous acid, which then liberates oxidant species which has antimicrobial benefits. 105 experimental formulations shown to be as good as chlorhexidine against plaque regrowth and showed same substantivity. • Side effects: Low pH of formulations cause dental erosion • To date no commercial products are availab le
89 ENZYMES: 1st group – not truly antimicrobial agents, more plaque removal agents- potential to disrupt early plaque matrix, dislodge bacteria from the tooth surface. • In late 1960s & early 1970s – dextranase, mutanase & various proteases – thought major breakthrough in dental plaque control • Had poor substantivity & unpleasant local side effects like mucosal erosion .
90 Dextranase: DEXTRAN high-molecular-weight polysaccharide synthesized by Streptococcus mutans. Action: microbial community development and proliferation, hence improving dental plaque’s structural integrity. Degradation of dextran by dextranase has been found to be one of the approaches to remove dental plaque and prevent further caries.
91 Bacterial dextranase-marine origin that are high salt tolerant and stable temperature 35.5°C , oral use- Khalikova E et al , Jiao YL et al 2014. fungal dextranase are reported to show higher optimal temperature in the range 50 to 60°C; hence, they might not be effective in oral use . Commercially available
92 2nd group : Glucose oxidase, amyloglucosidase enhanced host defense mechanism - glucose oxidase & amyloglucosidase • Catalyzed conversion of endogenous & exogenous thiocyanate to hypothiocyanite via salivary lactoperoxydase system • Hypothiocyanite produces inhibitory effects upon oral bacteria, particularly streptococci by interfering with their metabolism • Toothpaste containing enzymes & thiocyanate but no convincing long-term studies of efficacy
94 POVIDONE IODINE: 1811, Bernard Courtois – Iodine 1880, Devaine – Bactericidal efficacy Late 1960s – Povidone iodine Mechanism: affinity for the cell membrane, thereby delivering free iodine directly to the bacterial cell surface. It has a broad spectrum of activity against bacteria, fungi, protozoa, and viruses.
95 The mouthwash has been shown to be effective in reducing plaque and gingivitis and may be a useful adjunct to routine oral hygiene . Absorption of significant levels of iodine through the oral mucosa may make this compound unsatisfactory for prolonged use in the oral cavity-Fergusson et al. Side effects Staining teeth/ tissues Thyroid dysfunction Allergic to iodine Pregnant & lactating mother
96 DISCLOSING AGENTS: liquid, tablet or lozenge from which contains a dye or other coloring agents. used for identifying bacterial plaque When applied to the teeth, the agents imparts its colour to soft deposits but can be rinsed easily from clean tooth surface . IDEAL PROPERTIES: Intensity of colour Duration of intensity Taste Irritation to mucous membrane Diffusibility Astringent and antiseptic property
97 Agents used for disclosing plaque Iodine preparations Skinners iodine solution Diluted tincture of iodine Mercurochrome preparations Mercurochrome solution Flavored mercurochrome disclosing solution Bismarck brown Mebromin Erythrosine Fast green Fluoresin Two tone solutions
newer
100 Methods of application
101 . . Mouth rinse antiplaque, antigingivitis, antitartar and antisensitivity properties American Dental Association recognizes that mouthrinse containing chlorhexidine and the Listerine formula is effective in controlling plaque and gingivitis- Mandel 1988. chlorhexidine, triclosan, cetylpyridinium chloride and essential oils -due to their proven effectiveness and safety and general lack of sensory negatives such as bitterness
102 DENTRIFICES: The main functions of toothpaste (in conjunction with tooth-brushing) are: minimizing build-up of plaque strengthening teeth against caries cleaning the teeth by removing stain removing food debris Freshening the mouth. Brushing must be carried out regularly, correctly and for a sufficient length of time (at least one minute twice a day) to be effective. Three minutes is probably the minimum for fully effective plaque rem oval.
Gum prevention tooth paste
104 Anticalculus agents Calculus control is effected by agents such as soluble pyrophosphates and zinc citrate –Mandel et al 1995
105 RECENT DEVELOPMENT OF ANTIPLAQUE AGENTS sugar-free chewing gum on plaque and clinical parameters of gingival inflammation: chlorhexidine tetrapalmitate (CHXTP): •Results showed CHXTP salt – low tendency to stain •Addition of polyvinylpyrrolidone allowed CHXTP to be retained longer in mouth Renato FM et al
106 green tea catechin mouthwash Grape seed extract (GSE) & amine fluoride (Fluorinol) combination – significant antiplaque & important antioxidant capacity A synergistic chlorhexidine/ chitosan combination for improved antiplaque strategies Azadirachta indica leaf extract gel
107 FUTURE CHALLENGES IN CHEMICAL PLAQUE CONTROL Probiotics- aims to achieve biological plaque control by eliminating pathogenic bacteria Vaccination against oral biofilm Plant /natural products Ozone irrigation
108 CONCLUSION: • In past 50 years – various antiplaque agents have been formulated. • Still Chlorhexidine remains gold standard by which other agents are standardized. • Delmopinol & Chitosan also shows promising prospects
109 Home message Chlorhexidine Addy et al substantivity
110 Carranza’s clinical periodontology 8th, 9th, 10th ,11 thedition Jan Lindhe Clinical periodontology & Implant dentistry 5th edition Renato FM, Lorena B, Natalia SJ, Antonio CP, Marcos AC, Magali M, Man CC. A nonstaining and tasteless hydrophobic salt of chlorhexidine. Journal of pharmaceutical sciences. 2011 Aug;100(8):3130-38. Addy.M . Clinical indications for use of chemical plaque control agents. Periodontology 2000, Vol. 15, , 52- 54 128. Yates R, Jenkins S, Newcombe R, Wade W, Moran J, Addy M. A 6-month home usage trial of a 1% chlorhexidine toothpaste. J Clin Periodontol. 1993; 20:130-8. Mohammed HN, MortezaT , Majid RM, Ali F, Fateme F, Mona M et al. Comparative study of 0.2% and 0.12% digluconate chlorhexidine mouth rinses on the level of dental staining and gingival indices. Dent Res J (Isfahan). 2012 May-Jun; 9: 305-8. R eferences
111 Hase JC, Attstrom R, Edwardsson S, Kelty E, Kisch J. 6- month use of 0.2% delmopinol hydrochloride in comparison with 0.2% chlorhexidine digluconate and placebo. J Clin Periodontol. 1998;25:746-53. M Raveendra Pai, Leelavathi D Acharya , N Udupa . Evaluation of antiplaque activity of Azadirachta indica leaf extract gel – a 6-week clinical study. Journal of Ethnopharmacology . 2004 Jan;90:99-103. EM Decker, C Von Ohle , R Weiger , I Wiech , M Brecx. A synergistic chlorhexidine/ chitosan combination for improved antiplaque strategies. Journal of Periodontal Research. 2005 Oct;40(5):373-7. PC Baehni , Y Takeuchi. Anti-plaque agents in the prevention of biofilm-associated oral diseases. Oral Diseases. 2003 Jun;9(s1):23-29. JM Tanzer , AM Slee , B Kamay , ER Scheer . In vitro evaluation of three iodine-containing compounds as antiplaque agents. Antimicrobial agents and chemotherapy. 1977 July;12:107-13. Kaur H, Jain S, Kaur A. Comparative evaluation of the antiplaque effectiveness of green tea catechin mouthwash with chlorhexidine gluconate. J Indian Soc Periodontol. 2014 Mar-Apr;18(2):178-82 Addy M, Moran J, Newcombe RG. Meta-analyses of studies of 0.2% delmopinol mouth rinse as an adjunct to gingival health and plaque control measures. J Clin Periodontol 2007; 34: 58–65 Jones.C.Chlorhexidine:is it still the gold standard? Periodontology 2000, Vol. 15, 1997, 55-62.