Chemotherapeutic Agents I

Antiplaque Agents

2

Overview

• Introduction

• History

• Terminology

• Classification of antiplaque agents

• Rationale of antiplaque agents

• Ideal Properties of Antiplaque agents

• Groups of agents used in antiplaque agents

- Systemic antimicrobials including antibiotics

- Enzymes

3

- Bisbiguanide

- Quaternary ammonium compounds

- Phenols and essential oils

- Natural products

- Oxygenating agents

- Metal salts

- Amine alcohols

- Detergents (Sodium lauryl sulfate)

- Salifluor

- Conclusions

- References

4

Introduction

• Epidemiologic studies - Supragingival plaque & chronic gingivitis – high correlation (Ash et al 1964)

• Clinical research – proof – Plaque primary etiologic factor in gingival inflammation (Loe et al 1965)

• Mainstay of primary & secondary prevention of perio disease – control of supragingival plaque (Hancock 1996)

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• Left undisturbed – supra gingival plaque reaches qualitative & quantitative level of bacterial complexity incompatible with gingival health gingivitis

• Any method of plaque control stop gingivitis

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• Mechanical tooth cleaning – toothbrushing with toothpaste – arguably most common & effective form of oral hygiene practice (Frandsen 1986, Jepsen 1998)

• Use of chemical agents – adjuncts & not replacements for conventional mechanical methods

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History of Oral Hygiene Products

• Terminology – Oral Hygiene Products - Recent

• Dates back 6000 years (Fischman 1997)

• Ebers Papyrus 1500 BC – recipes for tooth powders, mouth rinses

• Formulations – Strange

• Hippocrates 480 BC

• Early toothpaste - Head of 1 hare & 3 whole mice, after taking out intestines of 2, mixing powder derived from burning animals with greasy wool, honey, aniseeds, myrrh & white wine – rubbed frequently on teeth

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• Mouth rinses – ingredients that had stimulating effect on salivary flow, breath odor masking & antimicrobial actions

• Alcohol based mouth rinses – popular with Romans – white wine & beer

• Urine – popular over many centuries – controversy over stale/ fresh urine – Cantabri/ Fauchard

• Arab preferred – children’s urine

• Romans – Arab urine

• Even to this day – individuals – own urine – virtue of urea content – Guidelines for Good Clinical Practice – ethical approval

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• Throughout centuries – most tooth powders, toothpastes & mouth rinses formulated – cosmetic reasons – tooth cleaning & breath freshening rather than control of dental & perio diseases

• Many formulations – very abrasive & / acidic substances

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• Some – antimicrobial ingredients – included arsenic & herbal materials

• Herbal extracts – increasingly used – little data to support for efficacy for gingivitis & none for caries

• Many agents – potential to cause local damage to tissues if not systemic toxicity – Aromatic sulfuric acid, mercuric perchloride, carbolic acid & formaldehyde (Dilling & Hallam 1936)

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• Biggest change to toothpastes – chemoparasitic theory of tooth decay of W.D. Miller 1890

• Introduction of agents into toothpaste which might influence this process & production of alkaline products

• Shortly after – at beginning of 20th century – various potassium & sodium salts were added to toothpaste as therapy for perio disease

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• 6000 years history of oral hygiene products – scientific evaluation – extremely recent event

• First ever double-blind randomized cross over design clinical trial in dentistry was 50 years ago (Cooke & Armitage 1960)

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TerminologyEuropean Workshop on Periodontology

• European Federation of Periodontology 1996

• Antimicrobial agents: chemicals that have bacteriostatic/ bactericidal effect in vitro that alone cannot be extrapolated to proven efficacy in vivo against plaque

• Plaque reducing/ Inhibitory agents: chemicals that have only been shown to reduce quantity & or affect quality of plaque which may/ may not be sufficient to influence gingivitis &/ or caries

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• Antiplaque agents: chemicals that have effect on plaque sufficient to benefit gingivitis & / or caries (Addy et al 1983)

• Antigingivitis agents: chemicals which reduce gingival inflammation without necessarily influencing bacterial plaque (includes anti-inflammatory agents)

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Rationale for chemical supragingival plaque control

• Improving oral hygiene & gingival health - Decreasing incidence of perio disease (Hugoson et al 1998)

• Tooth cleaning is largely influenced by compliance & dexterity of individual

• Individual brushing 2 mins – only around half of plaque removal (de la Rosa et al 1979)

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• Long term perio T/t follow up – success dependent on maintaining plaque levels (Axelsson & Lindhe 1981)

• Mechanical plaque control aims – maintaining plaque level quantitatively/ qualitatively compatible with health & not bacteria free

• To overcome deficiencies in mechanical tooth cleaning adjunctive use of chemicals

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Approaches to chemical supragingival plaque control

• Action of chemicals could fit into 4 categories

1.Antiadhesive

2.Antimicrobial

3.Plaque removal

4.Antipathogenic

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• Fig. 36-1 Bacterial succession plaque formation. There is increasing mass and bacterial complexity as plaque bacteria attach and proliferate. Ideal sites of action for chemicals which might infl uence plaque accumulation are shown. Acknowledgment to Dr. William Wade for permission to publish this diagram

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Antiadhesive agents

• Used in industry, domestically & environment

• Prevent attachment & devt of variety of biofilms

• Described as Antifouling agents

• Such applications – too toxic/ ineffective against dental bacteria plaques

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• Act at pellicle surface to prevent initial attachment of primary plaque forming bacteria

• To date – no effective formulations

• amine alcohol, delmopinol – appears to interfere with bacterial matrix formation fits somewhere between concepts of antiadhesion & plaque removal – Effective (Collaert et al 1992; Claydon et al 1996)

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Antimicrobial Agents

• Inhibit plaque formation by 1 of 2 mechanisms – alone/ combined

• 1st – inhibition of bacterial proliferation directed at plaque forming bacteria – could exert their effects either at pellicle coated tooth surface before primary plaque formers attach or after attachment but before division of these bacteria

• Plaque inhibitory effect – bacteriostatic

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• 2nd effect – bactericidal whereby antimicrobial agent destroys all of mo’s either attaching or already attached to tooth

• Bactericidal effect would have to be absolute &/ or persistent else other bacteria within oral environment would colonize tooth surface immediately following loss of bactericidal effect & biofilm reestablished

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Plaque Removal Agents

• Idea of Chemical agent – act as toothbrush + remove bacteria Chemical toothbrush

• Agents expected to remove bacterial deposits & commonly used at home - Hypochlorites

• Such agents – toxic

• Nearest success – Enzymes - directed at both:

• Pellicle e.g. proteases or

• Bacterial matrices e.g. dextranase and mutanase

• Potentially effective - Lacked substantivity within oral cavity & had local side effects

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Antipathogenic agents

• Theoretically possible – agent that inhibit expression of their pathogenicity without necessarily destroying microorganisms

• In some respect – Bacteriostatic Antimicrobial agents achieve such results

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Vehicles for delivery of chemical agents

• Toothpaste

• Mouth rinses

• Spray

• Irrigators

• Chewing gum

• Varnishes

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Chemical plaque control agents

• Over 5 decades Chemical agents to control plaque – intense interest & subject of many detailed reviews since 1980 (Hull 1980, Addy 1986, Kornman 1986, Mandel 1988; Gjermo 1989, Addy et al 1994, Heasman & Seymour 1994, Jackson 1997, Eley 1999)

• Mostly antiseptic/ antimicrobial

• Success – extremely variable

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• Most effective plaque inhibitory agents in antiseptic or antimicrobial group are those showing persistence of action in mouth measured in hours (Jones 1997)

• Termed as substantivity (Kornman 1986): ability to attach to and be retained by oral surfaces with slow release of active agent over time

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• Substantivity dependent on several factors:

Adsorption and prolonged retention on oral surfaces including, importantly, pellicle-coated teeth

Maintenance of antimicrobial activity once adsorbed primarily through a bacteriostatic action against primary plaque-forming bacteria

Minimal or slow neutralization of antimicrobial activity within oral environment or slow desorption from surfaces

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Ideal properties of antiplaque agents

• Eliminate pathogenic bacteria only

• Prevent development of resistant bacteria

• Exhibit substantivity

• Safe to oral tissues at recommended dosage and concentration

• Significantly reduce plaque and gingivitis

• Inhibit calcification of plaque

• Do not stain teeth or alter taste

• No adverse effect on teeth or restorations

• Easy to use and inexpensive

(Brall and Brownstein 1988)

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Classification

• Agents that could inhibit development/ maturation of supragingival plaque – classified according to possible mechanisms of action:

1.Anti-adhesive

2.Antimicrobial

3.Plaque removal

4.Antipathogenic

(Addy & Moran 1997)

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• Categorized according to their antimicrobial effect and substantivity (Kornman 1986)

First generation agents:

• Capable of reducing plaque scores by about 20- 50% & efficacy is limited by poor retention in mouth

Antibiotics

Phenols

Quaternary ammonium compounds

Sanguinarine

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• Second generation agents:

• More effectively retained by oral tissues and slow release properties provide reduction in plaque scores between 70 and 90%

• Eg: bisbiguanides

• 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

• Eg: amine alcohols

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Group Example of Agents

Action Used now/ Product

Antibiotics PenicillinVancomycinKanamycinNiddamycinSpiromycin

Antimicrobial No

Enzymes ProteaseLipaseNucleaseDextranaseMutanase

Plaque removal No

Glucose oxidaseAmyloglucosidase

Antimicrobial YesToothpaste

Bisbiguanide antiseptics

ChlorhexidineAlexidineOctenidine

Antimicrobial YesMouthrinseSprayGelToothpasteChewing gumVarnish

Quaternary NH4 Compounds

Cetylpyridinium chlorideBenzalconium chloride

Antimicrobial YesMouthrinse

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Group Example of Agents Action Used now/ Product

Phenols & essential oils

ThymolHexylresorcinol, Ecalyptol

Antimicrobial YesMouthrinseToothpasteTriclosan Anti-

inflammatory

Natural products Sanguinarine Antimicrobial No

Fluorides Sodium fluorideSodium monofluorophosphateStannous fluoride, Amine fluoride

Antimicrobial YesToothpasteMouthrinse, Gel

Metal Salts Tin, Zinc, Copper

Antimicrobial Yes, ToothpasteMouthrinse, Gel

Oxygenating agents

Hydrogen peroxideSodium peroxyborateSodium peroxycarbonate

Antimicrobial? Plaque removal

YesMouthrinse

Detergents Sodium lauryl sulfate Antimicrobial? Plaque removal

YesToothpasteMouthrinse

Amine alcohols OctapinolDelmopinol

Plaque matrixInhibition

NoYesToothpasteMouthrinse

Salicylanide Salifluor Antimicrobial & antiinflammatory

No

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Systemic antimicrobials including antibiotics

• Despite evidence for efficacy – systemic antimicrobials used in past (as topical/ systemic - 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)

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Enzymes

• Addy 1986

• Based upon theory that enzymes would break down matrix of already formed plaque

• Certain proteolytic enzymes would be bactericidal to plaque organisms & act as disinfectants when applied topically in oral cavity

• Fall into two groups

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• First group - not truly antimicrobial agents but more plaque removal agents - potential to disrupt early plaque matrix, thereby dislodging bacteria from 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

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• Second group - enhanced host defense mechanism - glucose oxidase & amyloglucosidase

• Catalysed 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

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Bisbiguanide antiseptics• Include chlorhexidine gluconate ,

octenidine & alexidine

• Most effective anti-plaque agents currently in use

• Are primarily second generation anti-plaque agents as they exhibit considerable substantivity and have broad antibacterial properties

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Chlorhexidine

• Cationic bisbiguanide - Developed in 1940s by Imperial Chemical Industries England - marketed in 1954 - antiseptic for skin wounds

• Available in 3 forms:

• digluconate,

• acetate &

• hydrochloride salts

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•Widely used in medicine and surgery including obstetrics, gynecology, urology, and presurgical skin preparation

• Initial use in dentistry - presurgical disinfection of mouth & in endodontics

• Application as anti plaque and calculus agent was suggested by Schroeder in 1969

• First definitive study on Chx was performed by Löe & Schiott (1970)

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• 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

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• Dicationic nature make it extremely interactive with anions - relevant to its efficacy, safety, local side effects & difficulties with formulation in products

• a long lasting antiseptic which is not neutralized by soaps, body fluids or other organic compounds

•

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• Broad antibacterial activity, low mammalian toxicity & strong affinity for binding to skin & mucous membranes

• Is most studied & effective antiseptic for plaque inhibition & prevention of gingivitis

• Nearest that research has come to identifying chemical agent that could be used as replacement for rather than adjunct to mechanical oral hygiene practices

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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

Toxicity:

• Relatively safe drug

• Poor systemic absorption

• Concentration > 2% may cause discomfort to skin

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Oral retention of chlorhexidine

• Efficacy with respect to other drugs is related with retention of drug in mouth

• Chx persistent bacteriostatic action lasting > 12 hours (Schiott et al 1970)

•When mouthrinse of 10 ml of 0.2% chlorhexidine is done or 1 min appx 30% drug is retained in mouth(Gjermo 1975)

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• Radio-labelled studies suggest slow release of antiseptic from surfaces (Bonesvoll et al. 1974a,b) - this was suggested to produce prolonged antibacterial milieu in mouth (Gjermo et al. 1974)

• Calcium ions from saliva are able to displace it from binding sites causing prolonged release and bacteriostatic effect

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Mechanism of action

• Potent antibacterial – but this alone does not explain antiplaque action

• Antibacterial activity:

• Binds strongly to bacterial cell membrane – alters integrity at low concentration leads to increased permeability & leakage of intracellular components (K+ ions)

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• At high conc causes precipatation of bacterial cytoplasm & cell death

• At low concentrations – bacteriostatic whereas at higher concentrations is rapidly bactericidal

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Antiplaque mode of action• Has ability to adsorb onto negatively

charged surfaces, such as bacterial cell walls, where it exerts its bacteriostatic and bactericidal effects

• Also binds to different surfaces within mouth (teeth and mucosa) and also to pellicle and saliva

• After a single rinse with chlorhexidine, saliva itself exhibits antibacterial activity for up to 5 hours , whereas persistence at oral surfaces has been shown to suppress salivary bacterial counts for over 12 hours

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• Small amount that binds to pellicle & enamel can then interfere with adherence of bacteria to tooth surface

• Rolla & Melsen (1977 ) postulated three mechanisms of plaque inhibition :Influence on pellicle formation by blocking

acidic groups on salivary glycoproteins – reducing protein adsorption to tooth surface

Influence on adsorption of plaque onto tooth surface by binding to bacterial surface in sublethal amounts

Influence on formation of plaque by precipitating agglutination factors in saliva & displacing calcium from plaque matrix

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• Any bacteria adhering to tooth surface are challenged by chlorhexidine at surface

• Depending on bacterial species, and amount attached to tooth surface, these microorganisms are either killed (bactericidal effect) or are simply prevented from multiplying (bacteriostatic effect)

• Plaque is prevented from forming because bacteria attaching to tooth surface cannot multiply

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Chlorhexidine as Gold standard• Superior antiplaque but due to superior

persistence of antibacterial effect - bactericidal & bacteriostatic

• Other antiseptics have only immediate effect & once removed from mouth plaque build up once again

• Some agents show same degree of persistence but may not possess bactericidal & bacteriostatic properties

• Dicationic nature with one charged end of molecule binding to tooth surface & other end to initiate interaction with bacterial membrane

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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

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Local side effects

• Flotra et al. 1971

1.Brown discoloration of teeth & some restorative materials & dorsum of tongue

2.Taste perturbation where salt taste appears to be preferentially affected (Lang et al. 1988) to leave food and drinks with a rather bland taste

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3)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

4) Unilateral or bilateral parotid swelling – extremely rare - negative pressure & aspiration into duct

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5)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

Chx also has Bitter taste - difficult to mask completely

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• Staining side effect limits long-term use of chlorhexidine in preventive dentistry (Flotra et al. 1971)

• Occurs with all products – rinse, gel, toothpastes, sprays

(Eriksen et al 1985, Addy & Moran 1995, Watts & Addy 2001)

• Proposed mechanisms for chlorhexidine staining:

1.Degradation of chx molecule to release parachloraniline

2.Catalysis of Maillard reactions

3.Protein denaturation with metal sulfide formation

4.Precipitation of anionic dietary chromogens

• Evidence indirect & inconclusive

Chlorhexidine staining

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• Dark yellow or brownish stain present on both natural & artificial teeth after few days of use of chlorhexidine

• More staining with higher concentration

• 3 possible mechanisms may be involved:

1.Carbohydrates and amino acids containing compounds present in acquired pellicle undergo series of polymerization reactions to produce pigmented substances called melanoidins- reactions are catalyzed by chlorhexidine which produces thick pellicle containing more amino groups than primary pellicle (Nordho 1979)

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2.Chlorhexidine denatures proteins in pellicle by 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)

3.Chlorhexidine reacts with ketones and aldehydes in dietary breakdown or intermediary products to form insoluble colored compounds ( Nordho 1971)

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• Locally bound antiseptics or metal ions on mucosa or teeth can react with polyphenols in dietary substances to produce staining

• Tea, coffee, and red wine are particularly chromogenic, but other foods and beverages will interact to produce various colored stains

• Can be used to assess patient compliance in use and activity of formulations

• AntiDiscoloration System – significant drawbacks

• Old adage – If it does not stain it does not work – still holds true

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Chlorhexidine products

• Mouth rinses:

• Aqueous solutions of 0.2% chlorhexidine – first available for twice daily rinse in Europe in 1970s

• Simultaneously 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

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• 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. 1987a)

• 0.2% and 0.12% chlorhexidine gels have become available

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• 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% mouthrinses (Kalaga et al. 1989a)

• Useful for physically and mentally handicapped groups - well received by individuals and their carers (Francis et al 1987a,b; Kalaga et al 1989b)

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• 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 markedly increased as was supragingival calculus formation

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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

• High-risk caries patients

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• Recurrent oral ulceration

• Removable and fixed orthodontic appliance wearers

• Denture stomatitis

• Oral malodor

• Immediate pre-operative chlorhexidine rinsing and irrigation

• Subgingival irrigation

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Quaternary ammonium compounds• Mandel 1988; Eley 1999

• Benzethonium chloride, benzalkonium chloride and Cetylpyridinium chloride (CPC) used as agents for plaque inhibition

• CPC most studied

• Are cationic antiseptics & surface active agents

• CPC at 0.05% conc used in wide variety of antiseptic mouth rinse products

• At oral pH these antiseptics are monocationic and adsorb readily and quantitatively, to a greater extent, than chx to oral surfaces (Bonesvoll & Gjermo 1978)

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• Molecules have net positive charge which reacts with negatively charged cell membrane phosphates

• More effective against gram positive than gram negative organisms – beneficial as antiplaque agent against early developing plaque

• Substantivity of cetylpyridinium chloride is only 3–5 hours (Roberts & Addy 1981) either loss of activity once adsorbed or rapid desorption

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• Efficacy of CPC – increased by doubling frequency of rinsing to 4 times per day (Bonsvoll & Gjermo 1978) – increased side effects & affect compliance

• Factors in saliva like calcium ions influence desorption of drugs

• Side effects:

Brownish discoloration of teeth

Yellow brown discoloration of tongue

Recurrent apthous type ulceration of oral mucosa

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• 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)

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Phenols and essential oils

• Mandel 1988, Jackson 1997, Eley 1999

• Used for over 100 years

• Used as disinfectants, antiseptics, antipruritics, antifungals and antimicrobials

• Both plaque inhibitory & antiinflammatory action – due to antioxidative activity (Firalti etl al 1994)

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• Most exert non specific antibacterial action dependent upon ability of drug to penetrate lipid component of cell walls of gram negative bacteria

• Also exhibit anti inflammatory properties which result from their ability to inhibit neutrophil chemotaxis , generation of neutrophil superoxide ion and production of prostaglandin synthetase

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• Charles et al 2004

• 6 month study - Compared with CHX – demonstrated equivalent effects on plaque & gingivitis without inherent side effects of chx

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• Because of low pH of product (4.3) – in vitro & in situ – erosion of dentine & enamel but less than orange juice (Addy et al 1991, Pontefract et al 2001)

• Combining essential oils with CPC attempted – promising results (Hunter et al 1994)

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• Listerine is an over the counter phenol preparation containing thymol, eucalyptol, methyl salicylate, benzoic acid and boric acid in hydro alcoholic vehicle

• Many short term and long term clinical trials demonstrated listerine as an effective inhibitor of plaque formation and development of gingivitis

• Non-ionic antimicrobial triclosan, a trichlora-2-hydroxy phenyl ether, has been widely used in a number of medicated products including antiperspirants and soaps

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• More recently, it has been formulated into toothpaste and mouth rinses

• Concentrations (0.2%) and dose (20 mg twice per day), triclosan has moderate plaque-inhibitory action and antimicrobial substantivity of around 5 hours (Jenkins et al. 1991 a,b)

• Activity of triclosan enhanced by addition of zinc citrate or co-polymer, polyvinylmethyl ether maleic acid (Gaffar et al

1992) – antimicrobial & retention

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Natural products• Mandel 1988, Eley 1999

• Herb and plant extracts

• Provide no greater benefits to oral hygiene and gingival health than do conventional fluoride toothpaste (Moran et al. 1991)

• Sanguinarine has been used in a number of formulations – Zinc salts incorporated – difficult to evaluate efficacy of Sanguinarine aloneIs a benzophenathridine alkaloid derived from Sanguinaria canadensis

• Has antimicrobial properties

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• Mouth rinses shown to increase likelihood of oral precancerous lesions ten-fold even after cessation of use

• Topically delivered tea tree oil - suggested to be of value in reducing gingival inflammation (Sookoulis & Hirsch 2004)

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Metal salts• Addy et al 1994; Jackson 19997

• Salts of certain metals - plaque inhibition

• Salts of zinc , tin , and copper have been studied and included in toothpaste formulations

• Zinc salts:

• Zinc ion as a plaque inhibitor was first described by Hanke in 1940

• Astringency of zinc at clinically active levels precludes use of many zinc salts

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• Zinc citrate has been combined with ionic antimicrobial triclosan in toothpaste form

• Combination has greater plaque inhibitory action than either constituent used separately and action dependent on concentration of constituents used

• Toothpaste containing zinc chloride shown to have significant anticalculus activity

• Zinc salts may be of value at reducing volatile sulfur compounds associated with oral malodor (Rosing et al 2002)

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• Tin salts:

• Inhibit plaque formation

• Stannous fluoride mouthrinses - 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 stannousfluoride was more due to tin ions although they have synergistic effect (Andreas et al 1974)

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• 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

• Disadvantage of metal salts:

Metallic taste

Dryness of mouth

Yellowish brown discoloration of teeth and tongue

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Oxygenating agents• Addy et al 1994

• Used as disinfectants

• Hydrogen peroxide has used for:

Supragingival plaque control

Bleach in tooth whitening

• Peroxyborate used in treatment of acute ulcerative gingivitis

• Products containing peroxyborate & peroxycarbonate were used with evidence of antimicrobial & plaque-inhibitory activity (Moran et al. 1995) - more long-term studies required – conclusive evidence

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Detergents• Sodium lauryl sulfate, common ingredient

in toothpaste and mouth rinse products

• Have antimicrobial activity (Jenkins et al. 1991b)

• Provide most of modest plaque inhibitory action of toothpaste (Addy et al. 1983)

• Alone - moderate substantivity, measured at between 5 and 7 hours, and plaque-inhibitory action similar to triclosan (Jenkins et al. 1991a,b)

• Detergent-only formulations are not available

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Amine alcohols • Group of compounds – do not truly fit into

antimicrobial/ antiseptic category

• Delmopinol – if correctly classified fit into antiadhesive agnet

• Considered as surfactant or wetting agent

• Low surface tension and lipophillic hydrophilic property can affect plaque growth without affecting ecological balance

• Comparatively low antimicrobial action

• Octopinol - first to be shown effective as antiplaque agent - withdrawn for toxicologic reasons

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• Delmopinol at 0.1% & 0.2% mouth rinses – shown to be effective against plaque & gingivitis in short term no oral hygiene & long term home use studies (Collaert et al 1992, Claydon et al 1996, Hase et al 1998, Lang et al 1998)

• Delmopinol hydrochloride - morpholine ethanol derivative with amphiphilic properties

• Inhibit plaque and gingivitis, despite being almost devoid of bactericidal or bacteriostatic actions in vitro or in vivo (Simonsson et al. 1991a, Attstrom et al. 1992, Rundegren et al. 1992a, Addy et al 2007)

100

• Mode of Action:

• Interfere with plaque matrix formation, reducing adherence of primary plaque-forming bacteria or of successional bacteria (Simonsson et al. 1991b)

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• Clinical studies in subjects who did not perform any oral hygiene procedures it has been shown to restrain dental plaque formation (Moran et al. 1992. Collaert et al. 1992a, Collaert

et al, 1992b, Hase et al. 1995a) & to dissolve newly formed plaque (Klinge et al. 1996)

• Experimentally induced gingivitis healed with delmopinol use (Collaert et al. 1992a, Coilaert et al. 1992b)

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• Addy et al 2007

• Conducted meta analysis

• Data from eight studies, from seven independent research groups in five European countries

• Delmopinol 0.2% mouthwash significantly effective adjunct measure for reducing plaque burden & severity of gingivitis

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• 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)

• 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

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Salifluor• Eley 1999

• 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

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Acidified sodium chlorite

• Yates et al 1997

• Sodium chlorite is reacted with protic acid to produce chlorous acid, which then liberates a range of higher oxidant species which has antimicrobial benefits

• Have broad range of antimicrobial action against bacteria, fungi, yeast, and viruses

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• 3 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 available

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Other antiseptics

• Addy 1986

• Most have little/ no effect in vivo

• Povidone iodine & Hexetidine

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Povidone Iodine

• At 1% has a substantivity of only 60 minutes (Addy & Wright 1978) and lacks appreciable plaque-inhibitory activity (Addy et al. 1977) or action in acute infections such as acute ulcerative gingivitis (Addy & Llewelyn 1978)

• Is without side effects but as rinse has potential to affect thyroid function adversely (Wray et al. 1978)

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Hexetidine

• Saturated pyrimidine

• At 0.1% - limited plaque inhibitory action (Bergenholtz & Hanstrom 1974, Chadwick et al 1991)

• Action enhanced by zinc salts

• Side effects uncommon – tooth staining, mucosal erosion

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• Double blind random

• 30 patients

• 4 treatment – Triphala, Hi ora, chx, Colgate Plax

• Concluded that Triphala and Hi ora similar to chx in efficacy & more than Plax

• Narayan A, Mendon C. Comparing the effect of different mouthrinses on de novo plaque formation. J Contemp Dent Pract. 2012;12:460-3.

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• Mild to moderate plaque levels & gingivitis patients

• 6 month, examiner blind random

• 3 groups – control, essential oil, CPC 0.05%

• Essential oils superior in reducing plaque & gingivitis

• Naresh CS, Marcelo WBA, Mei MW, James Q, Christine HC. Superiority of an essential oil mouthrinse when compared with a 0.05% cetylpyridinium chloride containing mouth rinse: a six month study. International Dental Journal. 2010 Jun;60(3):175-80.

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RS Keukenmeester, DE Slot, MS Putt and GA Van der Weijden. The effect of medicated, sugar-free chewing gum on plaque and clinical parameters of gingival inflammation: a systemic review. International Journal of dental hygiene. 2014 Feb;12(1):2-16.• Medline-PubMed, Cochrane Central &

EMBASE database

• Studies included use of intervention of medicated sugar free chewing gum containing antimicrobial agents or herbal extracts compared with control gum

• Most chewing gums – positive effect with respect to plaque & gingivitis scores – best for CHX gum – beneficial effect on plaque inhibition

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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.• Though CHX most effective & widely used – its side effects limit long term usage

• Less water soluble tetracation salt of CHX – chlorhexidine tetrapalmitate (CHXTP)

• Results showed CHXTP salt – very active against S.mutans, no interference on taste perception & low tendency to stain

• chlorhexidine digluconate better retention in saliva

• Addition of polyvinylpyrrolidone allowed CHXTP to be retained longer in mouth

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• 1 month double blind random

• With 0.05% CPC or without

• PI & GI

• Results show limited benefits as adjuncts to unsupervised oralhygiene in reducing plaque accumulation & no effect on gingivitis

• M Rioboo, V Garcia, J Serrano, A O’ Connor, D Herrera, M Sanz. Clinical and microbiological efficacy of an anitmicrobial mouth rinse containing 0.05 % cetylpyridinum chloride in patients with gingivitis. International Journal of Dental Hygiene. 2012 May;10(2):98-106.

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• A Furiga, C Roques, C Badet. Preventive effects of an original combination of grape seed polyphenols with amine fluoride on dental biofilm formation and oxidative damage by oral bacteria. Journal of applied microbiology. 2014;116(4):761-71.

• In vitro study

• Grape seed extract (GSE) & amine fluoride (Fluorinol) combination – significant antiplaque & important antioxidant capacity

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• 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.

• 18-25 years - 30 participants – 15 each

• 0.25% green tea catechin mouthwash & 0.12% CHX

• Phase I & phase II – 15 days X 2

• Difference between plaque scores not significant

• Results of plaque reduction - comparable

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• In preclinical biofilm model – bacteria suspended in sterile human saliva allowed to attach to human enamel slides for 60 mins

• Chx 0.1 % & chitosan 0.2% for 2 mins

• Chitosan – linear polysaccharide (sugar) composed of randomly distributed glucosamine – obtained by treating shrimp & other crustacean shells with alkali sodium hydroxide

• Concluded – new CHX formulation unifying bioadhesive property of chitosan with antibacterial activity of CHX had superior antiplaque effect than CHX alone

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.

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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.

• Effectiveness of Neem extract mucoadhesive gel

• Male 20-30 years with 0.2% CHX gluconate as positive control

• 6 weeks

• Total decrease in S. mutans & Lactobacilli salivary bacterial count & reduced PI - significant than CHX

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Mohammed HN, Morteza T, 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.

• Double blind - 60 patients – 17-56 years - with moderate to severe gingivitis

• 3 groups: I - placebo, II - 0.12 %, III – 0.2%

• Rinse twice daily after brushing

• 0 days & 14 days – PI, GI, BI & SI

• PI, GI - Improved in comparison to placebo

• BI – better/ more efficient with 0.2 % - not significant

• More staining with 0.2%

• Concluded – lower conc of CHX prescribed - decreased side effects & high conc not more effective in controlling plaque & gingivitis

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Conclusion

• In past 50 years – various antiplaque agents have been formulated

• Still Chlorhexidine remains gold standard by which other agents are standardized

• Delmopinol & Chitosan show promising prospects

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References

• Carranza’s clinical periodontology 8th, 9th, 10th edition

• 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, 1997, 52-54

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• 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, Morteza T, 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.

• 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.

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• 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.

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• 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.

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• 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.

THANK YOU

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