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Santa Cruz I, Herrera D. Antiplaque and antigingivitis toothpastes

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Santa Cruz I, Herrera D. Antiplaque and antigingivitis toothpastes

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Dentifrices are a general term used to describe preparations that are used together with a toothbrush with the purpose to clean and/or polish the teeth. Active toothpastes were first formulated in the 1950s and included ingredients such as urea, enzymes, ammonium phosphate, sodium lauryl sarcosinate and stannous fluoride. Later, therapeutic agents were included. Today's toothpastes have two objectives: to help the toothbrush in cleaning the tooth surface and to provide a therapeutic effect. The therapeutic effect may have an antiplaque or anti-inflammatory basis when the nature of the agents is antimicrobial. Plaque inhibitory and antiplaque activity of toothpastes used for chemical plaque control is evaluated in distinct consecutive stages, the last being home use randomized clinical trials of at least 6 months' duration. In this chapter, the scientific evidence supporting the use of the most common antiplaque agents, included in toothpaste formulations, is reviewed, with a special emphasis on 6-month clinical trials, and systematic reviews with meta-analyses of the mentioned studies. Among the active agents, the following have been included in toothpastes: enzymes, amine alcohols, herbal or natural products, triclosan, bisbiguanides (chlorhexidine), quaternary ammonium compounds (cetylpyridinium chloride) and different metal salts (zinc salts, stannous fluoride, stannous fluoride with amine fluoride). Dentifrices are the ideal vehicles for any active ingredient used as an oral health preventive measure since they are used in combination with toothbrushing, which is the most frequently employed oral hygiene method. The most important indications of dentifrices with active ingredients are associated with long-term use to prevent bacterial biofilm formation, mostly in gingivitis patients or in patients on supportive periodontal therapy.
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Abstract
Dentifrices are a general term used to describe prepara-
tions that are used together with a toothbrush with the
purpose to clean and/or polish the teeth. Active tooth-
pastes were first formulated in the 1950s and included
ingredients such as urea, enzymes, ammonium phos-
phate, sodium lauryl sarcosinate and stannous fluoride.
Later, therapeutic agents were included. Today’s tooth-
pastes have two objectives: to help the toothbrush in
cleaning the tooth surface and to provide a therapeutic
effect. The therapeutic effect may have an antiplaque or
anti-inflammatory basis when the nature of the agents is
antimicrobial. Plaque inhibitory and antiplaque activity
of toothpastes used for chemical plaque control is evalu-
ated in distinct consecutive stages, the last being home
use randomized clinical trials of at least 6 months’ dura-
tion. In this chapter, the scientific evidence supporting
the use of the most common antiplaque agents, included
in toothpaste formulations, is reviewed, with a special
emphasis on 6-month clinical trials, and systematic re-
views with meta-analyses of the mentioned studies.
Among the active agents, the following have been in-
cluded in toothpastes: enzymes, amine alcohols, herbal
or natural products, triclosan, bisbiguanides (chlorhexi-
dine), quaternary ammonium compounds (cetylpyridini-
um chloride) and different metal salts (zinc salts, stan-
nous fluoride, stannous fluoride with amine fluoride).
Dentifrices are the ideal vehicles for any active ingredient
used as an oral health preventive measure since they are
used in combination with toothbrushing, which is the
most frequently employed oral hygiene method. The
most important indications of dentifrices with active in-
gredients are associated with long-term use to prevent
bacterial biofilm formation, mostly in gingivitis patients
or in patients on supportive periodontal therapy.
Copyright © 2013 S. Karger AG, Basel
Dentifrices are a general term used to describe
preparations that are used together with a tooth-
brush with the purpose to clean and/or polish the
teeth. Dentifrices can be prepared as powders, gels
or toothpastes depending on the water content.
Toothpastes usually, but not necessarily, have high
water content, while powders have almost none.
In gels, most of the water content is replaced by a
humectant. In the present chapter, the terms den-
tifrice and toothpaste are used indistinctively.
Human beings were always conscious of the
importance of using toothpaste as part of oral hy-
giene practices. In fact, the first known tooth
cream was reported in Egypt, back in 3000–5000
van Loveren C (ed): Toothpastes. Monogr Oral Sci. Basel, Karger, 2013, vol 23, pp 27–44
DOI: 10.1159/000350465
Antiplaque and Antigingivitis Toothpastes
Mariano Sanz · Jorge Serrano · Margarita Iniesta · Isabel Santa Cruz ·
David Herrera
Etiology and Therapy of Periodontal Diseases Research Group, Faculty of Odontology, University Complutense,
Madrid, Spain
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van Loveren C (ed): Toothpastes. Monogr Oral Sci. Basel, Karger, 2013, vol 23, pp 2744
DOI: 10.1159/000350465
28
Sanz · Serrano · Iniesta · SantaCruz · Herrera
BC. Archaeological research has also suggested
that Greek and Roman civilizations used a powder
from cru shed bones from different animals as a
dentifrice. Around 500 BC, Chinese added flavor-
ings to the powders, such as ginseng and other
herbs. The modern era of therapeutically active
toothpastes, however, did not start until the 1950s,
when the first chemically active ingredients were
added, such as urea, enzymes, ammonium phos-
phate, sodium lauryl sarcosinate and stannous
fluoride.
Overall, modern toothpastes have both cos-
metic and therapeutic objectives: to help the
toothbrush in cleaning the tooth surface and pro-
vide a fresh breath (the cosmetic effect) and to
provide a therapeutic effect, mainly through anti-
caries, antihalitosis, antiplaque or anti-inflamma-
tory effects.
Composition of Toothpastes
Toothpastes are formulated by combining multi-
ple ingredients, and special attention must be paid
to avoid the possible interactions that may occur
among them. Among the ingredients that are usu-
ally part of a dentifrice formulation, the most im-
portant are listed in table1 [see the chapter by Lip-
pert for more details, see page 1–14]. In addition,
different active agents, being antimicrobial in na-
ture, have been included in toothpastes to provide
a therapeutic effect aiming to help in controlling
plaque and gingivitis. The adjunctive use of these
toothpastes may increase the efficacy of tooth-
brushing alone since the mechanical action of the
toothbrush will reduce the amount of biofilm and
disrupt its structure, thus facilitating the pharma-
cological mechanism of action of the toothpaste
formulation [1]. Among the active agents, the
following have been included in toothpastes:
enzymes, amine alcohols, natural products, tri-
closan, bisbiguanides (chlorhexidine, CHX), qua-
ternary ammonium compounds (cetylpyridinium
chloride, CPC) and different metal salts (zinc
salts, stannous fluoride, stannous fluoride with
amine fluoride, AmF).
The present review will also consider gels, if
they are used together with toothbrushing, as part
of plaque control. Since gels do not include abra-
sives or detergents, they are easier to formulate,
but their pharmacokinetics are less predictable.
In addition, both dentifrices and gels lack the
ability to access difficult to reach areas, such as the
tonsils, the dorsum of the tongue, etc.
Mechanisms of Action and Classification of
the Active Ingredients
Oral hygiene products used for chemical plaque
control have been categorized according to their
mechanism of action [2] as: (a) antimicrobial ag-
ents, when demonstrating a bacteriostatic or bacte-
ricidal effect in vitro; (b) plaque-reducing/inhibi-
tory agents, when demonstrating an in vivo signifi-
cant quantitative or qualitative effect on plaque
levels, which may not have a significant effect on
gingivitis and/or caries; (c) antiplaque agents, when
demonstrating an in vivo significant effect on pla-
que levels sufficient to achieve a significant benefit
in terms of gingivitis and/or caries control; (d) an-
tigingivitis agents, when demonstrating an in vivo
significant reduction in gingival inflammation
without, necessarily, reducing dental plaque levels.
The previous definitions are widely accepted
in Europe, but in North America the term anti-
plaque refers more often to agents capable of sig-
nificantly reducing plaque levels and antigingivi-
tis to agents capable of significantly reducing gin-
givitis levels.
Antiplaque activity may be achieved by differ-
ent mechanisms of action: (a) by preventing bac-
terial adhesion; (b) by limiting bacterial growth
and/or coaggregation; (c) by disrupting an al-
ready established biofilm; (d) by altering the com-
position and/or pathogenicity of the biofilm (see
fig.1). Its efficacy should be demonstrated in well-
designed clinical trials through quantitative (re-
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van Loveren C (ed): Toothpastes. Monogr Oral Sci. Basel, Karger, 2013, vol 23, pp 2744
DOI: 10.1159/000350465
Antiplaque and Antigingivitis Toothpastes
29
duction of the number of microorganisms) and/
or qualitative (altering the vitality of the biofilm)
effects [1].
Evaluation of the Plaque Inhibitory and
Antiplaque Activity of Toothpastes
In order to demonstrate the plaque inhibitory and
antiplaque activity of toothpastes used for chemi-
cal plaque control, different consecutive stages of
evaluation have been proposed, the last being the
home use randomized clinical trial of at least
6-months’ duration [3].
In vitro Studies
Toothpaste formulations including active agents
combine different ingredients that may interact
among themselves and lose their activity. It is there-
fore important to test the in vitro bioavailability of
the active agents, as well as their adsorption to dif-
ferent surfaces. In vitro studies evaluating product
Table 1. Toothpaste ingredients, adapted from Davies et al. [168]
Abrasives Surfactants Humectants
Alumina
Aluminium trihydrate
Bentonite
Calcium carbonate
Calcium pyrophosphate
Dicalcium phosphate
Kaolin
Methacrylate
Perlite (a natural volcanic glass)
Polyethylene
Pumice
Silica
Sodium bicarbonate
Sodium metaphosphate
Amine fluorides
Dioctyl sodium
sulfosuccinate
Sodium lauryl sulfate
Sodium N lauryl sarcosinate
Sodium stearyl fumarate
Sodium stearyl lactate
Sodium lauryl sulfoacetate
Glycerol
PEG 8 (polyoxyethylene
glycol esters)
Pentatol
PPG (polypropylene
glycol ethers)
Sorbitol
Water
Xylitol
Thickeners Flavors Preservatives
Carbopols
Carboxymethyl cellulose
Carrageenan
Hydroxyethyl cellulose
Plant extracts (alginate, guar gum, gum arabic)
Silica thickeners
Sodium alginate
Sodium aluminum silicates Viscarine
Xanthan gum
Aniseed
Clove oil
Eucalyptus
Fennel
Menthol
Peppermint
Spearmint
Vanilla
Wintergreen
Alcohols
Benzoic acid
Ethyl parabens
Formaldehyde
Methylparabens
Phenolics (methyl, ethyl, propyl)
Polyaminopropyl biguanide
Colors Film agents Sweeteners
Chlorophyll
Titanium dioxide
Cyclomethicone
Dimethicone
Polydimethylsiloxane
Siliglycol
Acesulfame
Aspartame
Saccharine
Sorbitol
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Sanz · Serrano · Iniesta · SantaCruz · Herrera
uptake are usually performed using different chem-
ical methodologies, such as spectrophotometry.
For evaluating the toothpaste antimicrobial
activity, different microbiological in vitro assays
have been developed. They usually measure the
minimum inhibitory concentrations and the
minimum bactericidal concentrations against a
battery of the most common oral bacterial spe-
cies. This information is usually of limited value,
since when using the toothpaste in vivo, there
are many different factors that affect its antibac-
terial activity and spectrum of action. Moreover,
this antibacterial activity is usually tested with
isolated bacteria as planktonic cells, while in the
oral environment bacteria are organized in com-
plex biofilms. Recently, in vitro biofilm models
have been developed for testing oral health prod-
ucts with antimicrobial activity, thus better sim-
ulating the real-life conditions [4–6].
In vivo Study Models
Similar to in vitro models, the product uptake is
evaluated in depot studies that assess the reten-
tion of the agent in the subject’s mouth after a
single use of the toothpaste. This is usually per-
formed by measuring the agent level in saliva or
in dental plaque. These results, however, do not
provide information on the activity of the
Fig. 1. Mechanisms of action of dentifrices. a Prevention of bacterial adhesion. b Interference with bacterial
growthand/or coaggregation. c Elimination of an already established biofilm. d Alteration of the pathogenicity of
the biofilm.
a b
c d
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van Loveren C (ed): Toothpastes. Monogr Oral Sci. Basel, Karger, 2013, vol 23, pp 2744
DOI: 10.1159/000350465
Antiplaque and Antigingivitis Toothpastes
31
product [7–12; see the chapter by Duckworth,
this vol.].
There are standardized in vivo models to eval-
uate the antiplaque activity of oral health prod-
ucts used for chemical plaque control. Although
most of these models have been developed for
assessing mouthrinse formulations, toothpastes
have also been studied by applying them in trays
or by transforming the toothpaste in an aqueous
solution or in slurry.
In vivo antimicrobial studies are usually de-
signed as crossover trials (with at least a placebo
and, preferably, also a positive control, normal-
ly a CHX mouthrinse, in which the amount of
bacteria in saliva is measured before and after a
single use of a tested formulation.
Plaque regrowth studies are also usually desig ned
as crossover trials (with at least a placebo and
preferably also a positive control), in which plaque
regrowth after a professional prophylaxis is mea-
sured for a short period of time (normally 3–4
days), and only the use of the tested toothpaste is
allowed as oral hygiene method (no toothbrush-
ing). In these studies, the plaque inhibitory capac-
ity of the toothpaste is tested [13–17].
Experimental gingivitis studies have the same
design as plaque regrowth studies but usually
utilize longer evaluation times (typically 12–28
days) and assess clinically relevant outcome va-
riables (plaque and gingivitis indices) [18, 19].
Experimental gingivitis studies can be also de-
signed as parallel studies since during this eval-
uation time, no mechanical hygiene is allowed.
In vivo biofilm study models assess the efficacy
of the toothpaste formulations in different sur-
faces, such as enamel, dentine or other materials,
which are included in devices inserted in the
subjects mouth during different evaluation peri-
ods. Once retrieved, the biofilm organized on th-
ese surfaces is analyzed and measured [20, 21].
Home Use Clinical Trials
It is a general consensus that the plaque inhibitory
and antiplaque activity of oral health products
needs to be demonstrated in long-term (at least
6months), home use, randomized clinical trials.
These studies not only demonstrate the efficacy of
the product, but also its safety, by evidencing the
lack of relevant side effects. In these studies, the
use of the tested formulations should be adjunc-
tive to mechanical plaque control (toothbrush-
ing). These home use clinical trials should have
certain characteristics to provide accepted results
[22]:
a Experimental design. They should be ade-
quately controlled (negative and/or positive
controls) and blinded (double blind, including
patients and examiner).
b Duration. They should be designed with a min-
imum of 6 months to allow for an adequate
evaluation of their long-term efficacy, being
able to compensate for the likely Hawthorne
effect [23] and to monitor the absence of rele-
vant adverse events.
c Microbiological evaluation. They should in-
clude the adequate microbiological methods
to assess the product’s antimicrobial activity as
well as the absence of microbiological adverse
effects, such as the overgrowth of pathogenic,
opportunist or resistant strains.
Concerning validity of clinical outcome mea-
sures, plaque and gingival indices are the primary
outcome variables in home use studies. They are
usually assessed with well-validated indices (al-
though most of them rely on a subjective evalua-
tion), although a previous training of the examin-
ers is mandatory with adequate intra- and inter-
examiner calibration trials.
Oral health products, when demonstrating
significant efficacy in terms of plaque and gingi-
vitis reductions in, at least, two 6-month indep-
endent clinical trials, have received a ‘seal of ap-
proval’ by relevant agencies, such as the Ameri-
can Dental Association and the Food and Drug
Administration.
In the following section, the scientific evidence
supporting the use of the most common agents
included in toothpaste formulations is reviewed,
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DOI: 10.1159/000350465
32
Sanz · Serrano · Iniesta · SantaCruz · Herrera
with special emphasis on 6-month, home use,
clinical trials and on systematic reviews with me-
ta-analyses of 6-month studies (see tables 2, 3).
Enzymes
Specific agents include glucose oxidase and
amyloglucosidase. Their mechanisms of action
rely on the catalyzation of thiocyanate into hy-
pothiocyanite through the salivary lactoperoxi-
dase system. Clinical studies with gingivitis pa-
tients have shown contradictory results, and
no long-term (6-month) studies are available
[24–27].
Amine Alcohols
Specific agents include delmopinol and octapi-
nol. Their mechanism of action is through the
inhibition and disruption of the biofilm extracel-
Table 3. Summary of meta-analyses of 6-month home use randomized clinical trials in terms of gingivitis levels
Active agent (vehicle) First author
and year
n WMD p value 95% CI Heterogeneity
p value I
2
, % method
Triclosan and copolymer
(dentifrice)
Gunsolley, 2006
Hioe, 2005
Davies, 2004
16
8
14
0.86
0.24
0.26
<0.001
<0.0001
<0.00001
NA
0.13–0.35
0.18–0.34
<0.001
<0.00001
<0.00001
98.3
96.5
random
random
NA
Triclosan and zinc citrate
(dentifrice)
Hioe, 2005
Gunsolley, 2006
4
1
10.8%
a
NA
<0.00001
NA
8.93–12.69
NA
0.48 0
NA
random
NA
Stannous fluoride
(dentifrice)
Gunsolley, 2006
Paraskevas, 2006
6
6
0.44
0.15
<0.001
<0.00001
NA
0.11–0.20
0.010
<0.00001
91.1 NA
random
a
Effect on bleeding.
Table 2. Summary of meta-analyses of 6-month home use randomized clinical trials in terms of plaque levels
Active agent (vehicle) First author
and year
n WMD p value 95% CI Heterogeneity
p value I
2
, % method
Triclosan and copolymer
(dentifrice)
Gunsolley, 2006
Hioe, 2005
Davies, 2004
17
9
11
0.82
0.48
0.48
<0.0001
<0.0001
<0.00001
NA
0.24–0.73
0.32–0.64
high
<0.00001
<0.00001
>75
a
97.2
95.7
random
random
random
Triclosan and zinc citrate
(dentifrice)
Hioe, 2005
Gunsolley, 2006
6
NA
0.07
NA
<0.00001
NA
0.05–0.10
NA
0.53 0
NA
random
NA
Stannous fluoride
(dentifrice)
Gunsolley, 2006
Paraskevas, 2006
5
4
0.17
0.31
significant
0.01
NA
0.07–0.54
low
<0.0001
<25
a
91.7
NA
random
n = Number of studies included in the meta-analyses; WMD = weighted mean difference between test and placebo
groups; CI = confidence interval; NA = not available.
a
Estimated.
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van Loveren C (ed): Toothpastes. Monogr Oral Sci. Basel, Karger, 2013, vol 23, pp 2744
DOI: 10.1159/000350465
Antiplaque and Antigingivitis Toothpastes
33
lular matrix, and therefore they are not anti -
microbial agents since they disrupt an already es-
tablished biofilm. They also inhibit glycan syn-
thesis by Streptococcus mutans [28, 29] and thus
reduce bacteria acid production [30]. Delmopinol
has been marketed as toothpaste in concentra-
tions of 0.2%, in combination with 0.11% fluoride
as sodium fluoride (NaF). It has been clinically
evaluated just as a mouthrinse at concentrations
of 0.1 and 0.2% [16, 31–34] but not as toothpaste.
Metal Salts: Zinc Salts
Specific agents include zinc lactate, zinc citrate,
zinc sulphate or zinc chloride. Zinc salts have
shown antibacterial action due to their ability to
inhibit bacterial adhesion, metabolic activity and
growth. Zinc products have been evaluated for
plaque control, but also focused on halitosis con-
trol [35–39; see the chapter by Dadamio et al., this
vol.], tartar control [40, 41; see the chapter by van
Loveren and Duckworth, this vol.], or healing
properties in presence of ulcers [42]. Some prod-
ucts have demonstrated some efficacy on plaque
[43] and gingivitis [44, 45]: a 12-week study re-
ported a 20.7% reduction in plaque and 38.1% in
gingivitis, of a 0.1% o-cymen-5-ol and 0.6% zinc
chloride dentifrice, when compared to a control
dentifrice (p < 0.0001) [44]; however, only one
6-month trial is available [45], demonstrating re-
ductions of 25.3% in plaque and 18.8% in gingivi-
tis, when compared to the placebo.
In summary, when they are used as single in-
gredients, they have limited effects on plaque; but
they may also be used in combination with other
active agents (triclosan, CPC, CHX), which may
improve substantivity and efficacy.
Metal Salts: Stannous Fluoride
Stannous fluoride has been included in dentifric-
es and gels since 1940s. The mechanism of action
of the stannous ion is through adherence to the
bacterial surface, inhibition of bacterial coloniza-
tion, penetration into the bacteria cytoplasm and
interference with the bacterial metabolism [46].
The combination of stannous and fluoride, chem-
ically SnF
2
, is difficult to formulate in oral hygiene
products due to the lack of stability of this formu-
lation in presence of water [47]. Several formula-
tions have been tested, but the two most com-
monly evaluated are the combination of stannous
fluoride and AmF (addressed in the following
section), and 0.454% stabilized stannous fluoride
combined or not with sodium hexametaphos-
phate (SHMP). Several 6-month studies have
been published, evaluating gel or dentifrice prod-
ucts, more frequently with the 0.454% SnF
2
for-
mulation [48–52], but also with SnF
2
plus SHMP
[53–55] and older formulations [56, 57]. There
are two published systematic reviews evaluating
their efficacy in randomized clinical trials. In one
of them, the 0.454% SnF
2
formulation provided
significant benefits in terms of gingivitis (weight-
ed mean difference, WMD, 0.441, p < 0.001, but
with significant heterogeneity, p = 0.010) [58]. In
the other systematic review [59], data pooling was
performed at the final study visit, assuming that
no differences were found at baseline, and there
was limited availability of data, which prevented
the meta-analysis. In addition, the results com-
bined different SnF
2
formulations, including the
combin ation with AmF. The results demonstrat-
ed signi ficant differences, favoring the test group,
in terms of gingival index (WMD –0.15), modi-
fied ging ival index (WMD –0.21) and plaque in-
dex (WMD–0.31), also demonstrating a signifi-
cant heterogeneity. Gels formulated with 0.4%
stannous fluoride have also been evaluated, re-
porting reductions in gingival inflammation and
in bleeding on probing [56, 60]. The observed ad-
ditional reductions in bleeding and gingival in-
flammation amounted for 67% and 50%, respec-
tively, as compared to the control, after 3 months
[60].
Metal Salts: Stannous Fluoride with Amine
Fluoride
AmF was developed in the 1950s at the Univer-
sity of Zurich. Its formulation in combination
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van Loveren C (ed): Toothpastes. Monogr Oral Sci. Basel, Karger, 2013, vol 23, pp 2744
DOI: 10.1159/000350465
34
Sanz · Serrano · Iniesta · SantaCruz · Herrera
with stannous fluoride (AmF/SnF
2
) has demon-
strated an increased bactericidal activity when
compared with AmF alone. Its antimicrobial
mechanism of action is through antiglycolytic ac-
tivities. The activity of AmF/SnF
2
formulated as
dentifrice lasts during 8 h after its use [61], al-
though clinical trials have not demonstrated a sig-
nificant benefit when used as dentifrice alone
[62–65]. When used in combination with a
mouthrinse, significant effects over plaque, but
not over gingivitis [65], have been shown: plaque
reductions versus baseline were 16%, (p < 0.001).
Natural Products
Specific agents include sanguinarine extract and
other herbal ingredients (chamomile, echinacea,
sage, myrrh, rhatany, peppermint oil). Sanguina-
rine is an alkaloid obtained from the plant San-
guinaria canadensis which has demonstrated low
bactericidal capacity in an in vitro biofilm model
[4], while its clinical evaluation has reported con-
tradictory results [66–68]. At least five home use,
6-month, oral hygiene trials were performed in
the 1980s and early 1990s, assessing sanguinarine
extract with zinc chloride, used as dentifrice [69,
70] or used in combination with mouthrinse [71–
73]. This combination reported significant reduc-
tions in terms of plaque and gingivitis: plaque re-
ductions versus placebo ranged between 30% [71]
and 13% [73]; for gingivitis, the respective range
was 39–16%.
Triclosan
Triclosan [5-chloro-2-(2, 4 dichlorophenoxy)
phenol] is a non-ionic bisphenolic, broad-spec-
trum antibacterial agent [74]. Triclosan has
beenwidely formulated in dentifrices usually in
combination with polyvinyl-methyl ether maleic
acid copolymer, zinc citrate or pyrophosphate,
in order to improve the substantivity and/or
the antimicrobial activity. With these formula-
tions, itcan be detected for up to 8 h in dental
plaque [75]. Triclosan has also demonstrated
anti- inflammatory effects [76–78] through the
inhibition of the cyclooxygenase and lipoxygen-
ase pathways, by reducing the synthesis of pros-
taglandins and l eukotrienes.
Three triclosan dentifrice formulations (tri-
closan with copolymer, triclosan with zinc ci-
trate, triclosan with pyrophosphate) have been
tested in 6-month, home use, randomized clini-
cal trials. A dentifrice containing triclosan and
zinc citrate was extensively evaluated in the
1990s [79–85]. The results of two systematic re-
views provide conflicting results. In one, a lim-
ited meta-analysis demonstrated a small but sig-
nificant effect on plaque (WMD –0.07, p <
0.00001) and a more important effect on gingival
bleeding reduction (WMD –10.81%, p < 0.00001)
[86]. Conversely, no significant differences were
observed in the other systematic review evaluat-
ing changes between baseline and end of study
[58]. A dentifrice with triclosan and copolymer
has also been extensively evaluated in 6-month
clinical trials [50, 79, 82, 87–99]. In a limited me-
ta-analysis over final visit values, a significant ef-
fect was observed on plaque using the Turesky
modification of the plaque index (WMD –0.48,
p < 0.0001) and on gingivitis using the Talbott
modification of the gingival index (WMD –0.24,
p < 0.0001). In both cases, significant heteroge-
neity was shown [86]. In another meta-analysis,
evaluating changes between baseline and final
visit, a significant effect in plaque was observed
(WMD 0.823), with significant differences in 14
out of the 18 included arms; a significant effect
was also observed for gingivitis (WMD 0.858).
In both cases, a significant heterogeneity was re-
ported [58]. A dentifrice containing triclosan
and pyrophosphate have been evaluated less fre-
quently [79, 80, 99, 100], and the results are con-
flicting, also demonstrating a significant hetero-
geneity [58].
Bisbiguanides: Chlorhexidine
CHX is an active agent against Gram-positive
and Gram-negative bacteria, yeasts and viruses,
including the human immunodeficiency and
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Antiplaque and Antigingivitis Toothpastes
35
hepatitis B viruses [101]. Its mechanism of action
is bacteriostatic at low concentrations, by in-
creasing the bacterial plasmatic membrane per-
meability [102, 103]. At higher concentrations, it
is bactericidal by inducing intracytoplasmic pre-
cipitation and cellular death [104, 105]. When
tested against biofilms, CHX has demonstrated
its capacity to penetrate and to actively alter the
biofilm formation and cause bacterial death [4,
106]. In addition to its antimicrobial effect, CHX
interferes with bacterial adhesion [104, 107–
110], interacts with salivary glycoproteins and
also reduces the activity of bacterial enzymes in-
volved in glycan production (glycosyl transferase
C) [111].
The CHX molecule is highly cationic and
binds reversibly to oral tissues [8, 9], evidencing a
slow release that allows for sustained antimicro-
bial effects for up to 12 h [112]. Due to its cation-
ic characteristic, this molecule is difficult to for-
mulate in dentifrices due to the risk of inactiva-
tion with other anionic ingredients. There are,
however, two published 6-month studies evaluat-
ing CHX-containing dentifrices: dentifrices with
1% CHX [113] and with 0.4% CHX in combina-
tion with zinc [114] demonstrated significant
benefits in terms of plaque and gingival inflam-
mation. The use of a 1% CHX dentifrice produced
19% of additional reduction in terms of plaque
and 7% in terms of gingival inflammation, as
compared to the control [113]. A 0.4% CHX den-
tifrice with zinc resulted in reductions of 27% and
12%, respectively, as compared with the control
[114].
CHX gels for use with a toothbrush or ap-
plied in trays are available at different concen-
trations, (0.1, 0.12, 0.2, 0.5 and 1%), although
the amount of CHX delivered when used with a
toothbrush is not predictable [115]. When ap-
plied in a dental tray, a reduction in the levels of
plaque and inflammation has been reported
[116–118], although the acceptance by patients
and therapists (used in disabled patients) was
not good [119]. CHX gels may also be used for
other purposes, such as prevention of alveolitis
after tooth extraction [120, 121]. Its use has also
been suggested as part of the full-mouth disin-
fection protocols, including tongue brushing
with 1% CHX gel for 1 min and subgingival ir-
rigation of pockets with 1% CHX gel [122, 123].
More recently, it has been evaluated in peri-im-
plant mucositis therapy [124], although with
limited effects.
Quaternary Ammonium Compounds
Specific agents include benzylconium chloride
and CPC. Their mechanisms of action rely on the
hydrophilic part of the CPC molecule that inter-
acts with the bacterial cell membrane, leading to
its disruption, alteration of the bacterial cell me-
tabolism growth inhibition and finally cell death
[125, 126]. CPC is a monocationic agent due the
positive charge of the mentioned active hydro-
philic part. This characteristic allows rapid ad-
sorption of this molecule to oral surfaces [127]
with a substantivity of approximately 3–5 h [128],
although it also rapidly loses its activity or be-
comes neutralized [127]. Its formulation is also
complex since it is easily inactivated by other in-
gredients, which makes the study of its bioavail-
ability important. There are no 6-month clinical
trials assessing the efficacy of CPC-containing
toothpastes.
Safety and Adverse Effects
One of the limitations of the use of toothpastes
with active ingredients is the risk of adverse ef-
fects and possible interactions with other ingredi-
ents.
Enzymes. No relevant adverse effects have
been described.
Amine alcohols. The most relevant side ef-
fects described are tooth staining and possible
occurrence of a transient sensation of numb-
ing and burning of the mucosa and/or the
tongue.
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Zinc salts. At low concentrations, no adverse
effects have been reported.
Stannous fluoride and stannous fluoride with
AmF. Their main limiting factor may be tooth
staining [65, 129, 130]. This limiting factor is
not associated with formulations including
SHMP.
Natural products. The use of sanguinarine has
been associated with oral leukoplakia [131].
Triclosan. There are no relevant side effects,
but the formation of a carcinogenic product
(chloroform) was demonstrated in an in vitro
study, when combining triclosan with the
free chlorine present in water [132]. In addi-
tion, a possible environmental hazard has
been suggested since triclosan is detected in
the food chain. No convincing evidence is
available to support the mentioned risks.
• CHX. Several adverse events have been re-
ported with the use of this molecule, includ-
ing: hypersensitivity reaction after oral use
[133], neurosensory deafness when the prod-
uct is placed in the middle ear [134], taste al-
terations and presence of a bitter taste [135,
136], uni-or bilateral parotid tumefaction
[137, 138], staining, either of teeth, mucosa,
tongue dorsum or restorations [137], muco-
sal erosion [139], or even alterations in the
wound healing process (suggested from in vi-
tro studies). In vivo studies, however, have
not found interference with the healing pro-
cess, but on the contrary, a better resolution
of the inflammation was reported [140].
Heating during long periods of time can in-
duce the formation of 4-chloroanilinine,
which has been shown to be cancerogenic
and mutagenic. No adverse microbiological
changes, including the overgrowth of oppor-
tunistic strains, are induced after long-term
use [112, 141, 142].
Quaternary ammonium compounds. The re-
ported adverse effects are similar, although
less frequent than with CHX formulations,
and include tooth and tongue staining, tran-
sient gingival irritation and aphthous ulcers in
some individuals [143]. In addition, no signif-
icant changes in the oral microbiota or over-
growth of opportunistic species have been ob-
served [144].
Interactions between Toothpaste Ingredients
The complexity of toothpaste formulations may
lead to the interference among ingredients, re-
sulting in a limited activity. The best known ex-
ample is CHX. CHX digluconate forms low solu-
bility salts with anions, such as phosphate, sul-
phate or chloride; therefore, anionic detergents
may reduce CHX activity when formulated in a
toothpaste [24]. CHX may interfere with abra-
sives, and it is incompatible with sodium mono-
fluorophosphate and other fluorides due to the
formation of non-soluble salts (in vitro) [145].
Anionic thickeners, such as carboxymethyl cellu-
lose, should not be used in a formulation with
CHX, requiring non-ionic thickeners, such as cel-
lulose ethers.
Among the other active agents, CPC is a
monocationic molecule, which may also be inhib-
ited by different toothpaste ingredients, especially
detergents [146].
Indications of Toothpastes with Plaque
Inhibitory and/or Antiplaque Activity
Dentifrices are the ideal vehicles for any active
ingredient used as an oral health preventive
measure, since they are used in combination
with toothbrushing, which is the most frequent-
ly employed oral hygiene method. However,
there are also a number of disadvantages, such
as the difficulties in their formulation due to the
likely interactions between the active agents and
the other dentifrice ingredients. Their pharma-
cokinetics are less predictable than those of
mouthrinses, and they will not reach to areas of
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Antiplaque and Antigingivitis Toothpastes
37
difficult access, such as the tonsils or the dorsum
of the tongue. Furthermore, in some specific sit-
uations, such as when used after surgical inter-
ventions or in disabled patients, their use to-
gether with toothbrushing might not be possible
since patients may be instructed not to brush or
they may not be able to brush.
Toothpastes with active ingredients, therefore,
should not be recommended in single-use appli-
cations (e.g. preoperative use) or in situations
where mechanical plaque control is suboptimal
or impossible. The most important indication is
their long-term use to prevent biofilm formation,
mostly in gingivitis patients or in patients on sup-
portive periodontal therapy.
There are specific recommendations for spe-
cial patient categories:
In patients with fixed or removable orth-
odontic appliances. A common strategy to
improve mechanical plaque removal in these
patients is the addition, as part of the oral hy-
giene regimen, of a chemotherapeutic antimi-
crobial agent. Amine/stannous fluoride [147]
or sanguinarine [71] in the form of mouth-
rinses combined with toothpastes or gels,
have been evaluated in clinical studies. Most
of these clinical studies have reported signifi-
cant benefits in the adjunctive use of these
products, although the magnitude of the re-
ported benefits might not have a clear clinical
relevance.
• In periodontitis patients. Together with an
adequate professional supportive periodon-
tal therapy program, chemical agents may be
recommended to improve biofilm control
and to decrease the risk of disease progre-
ssion. A careful consideration of the risk-
benefit ratio should be made since these pa-
tients will be in supportive therapy for life. A
dentifrice with triclosan and copolymer eval-
uated for 2 years demonstrated a significant
reduction in the presence of deep pockets
and sites with clinical attachment and bone
loss [148–150].
In patients with dental implants. The use of
different agents (CHX, triclosan, stannous
fluoride) may help to control biofilms and de-
crease the risk of peri-implant diseases [151–
153]. In a randomized trial, triclosan/copoly-
mer significantly improved clinical and mi-
crobiological variables, as compared with a
fluoride dentifrice, after 6 months [153].
In the general population. Its main use should
be the treatment of gingivitis by reaching a bal-
ance between the biofilm and the host response,
thus maintaining a gingival health status. Den-
tifrices containing triclosan and copolymer [58,
86] as well as stannous fluoride [58, 130] have
demonstrated antiplaque efficacy in 6-month
clinical trials. The available data from the sys-
tematic reviews show the clinical benefit of its
daily use when compared with the provision of
oral hygiene instructions. In spite of these ben-
efits, the daily usage of antiseptic products in
the general population is still a subject of con-
troversy since optimal results may be also
achieved without the adjunctive antiseptic [58].
Other indications of the long-term use of
toothpastes with antimicrobial ingredients may
be the prevention of the other oral conditions.
In caries prevention. Dentifrices with triclosan
and copolymer or a zinc salt have demonstrat-
ed anticaries activity [154] even in long-term
studies [155]. In high-risk patients, amine and
stannous fluoride may also be recommended
based on the proven remineralization and an-
ticaries action [156, 157].
In the prevention of recurrent aphthous ul-
cers. CHX usage may reduce incidence, dura-
tion and severity, including ulcers in patients
with fixed orthodontic appliances [158]. Tri-
closan formulation may also decrease the inci-
dence of oral ulcers [159].
In halitosis therapy and secondary prevention.
Different chemical agents and formulations
have been evaluated, with two main aims: anti-
bacterial and interference with volatilization of
odoriferous compounds. Among the most eval-
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uated agents, the following may be highlighted:
triclosan with zinc or copolymer [160–163], or
CHX, especially if combined with zinc salts and
CPC in a mouthrinse formulation [164–166].
In order to be effective, these agents need to be
used in conjunction with adequate oral hygiene
and tongue scrapping or brushing [167; see the
chapter by Dadamio et al., this vol.].
Conclusions
Dentifrices are normally used in combination with
toothbrushing, providing a cosmetic (cleaning,
fresh breath) and often also a therapeutic (caries,
periodontal diseases, halitosis control) benefit.
Different ingredients have been included as
active components in dentifrice formulations
depending on the therapeutic claim. When the
objective is the control of plaque and gingivitis,
enzymes, amine alcohols, herbal extracts, triclo-
san, bisbiguanides, quaternary ammonium com-
pounds and metal salts, have been utilized. De-
pending on their activity, they can be categorized
as antimicrobial, plaque inhibitory, antiplaque
or antigingivitis. Antiplaque agents are those
able to significantly affect plaque and gingivitis,
and they should be preferred in the treatment of
gingivitis and the prevention of periodontal dis-
eases. The efficacy of these products should be
demonstrated in well-designed, 6-month, home
use, randomized clinical trials.
Dentifrices based on zinc salts have shown
only limited effects on plaque. However, they may
improve the substantivity and efficacy of other
active agents when formulated together.
Stabilized stannous fluoride formulations,
especially if combined with SHMP, have shown
reductions in both plaque and gingivitis. Stan-
nous fluoride in combination with AmF may re-
duce plaque levels, but only if combined with a
mouthrinse with the same active ingredients.
A dentifrice with sanguinarine extract has
demonstrated conflicting results, but its clinical
use is not recommended due to its association
with leukoplakia.
Triclosan-based products have an effect on
plaque and inflammation, but the results when
comparing different studies and formulations
have shown high heterogeneity. The best results
have been demonstrated in a formulation with a
proprietary copolymer that enhances substan-
tivity.
CHX-based (0.1% or 0.4% with zinc) denti-
frices have produced significant reductions in
plaque and gingivitis, but are usually associated
with adverse effects, especially tooth staining.
They may also be used for other indications such
as alveolitis after tooth extraction, full-mouth
disinfection protocols or peri-implant disease
therapy.
Dentifrices represent the ideal vehicle for the
application of active agents in the prevention
(and therapy) of the most prevalent oral diseas-
es, caries and periodontal diseases, since they are
used in combination with toothbrushing, per-
haps the most compliant behavior of modern
human beings. Dentifrices, however, can be pro-
duced with complex formulations that may in-
terfere with the activity of the therapeutic agents,
and therefore the efficacy of any newly marketed
dentifrice should be tested in well-designed ran-
domized clinical trials. Formulations with triclo-
san (especially with copolymer), stannous fluo-
ride (with SHMP) and CHX have demonstrated
significant antiplaque efficacy. These products
are clearly indicated in high-risk patient groups
such as periodontitis patients, subjects with den-
tal implants or patients with fixed orthodontic
appliances. The daily usage of these antiseptic
products in the general population is still a sub-
ject of controversy since optimal results may
also be achieved without the adjunctive active
ingredient.
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Antiplaque and Antigingivitis Toothpastes
39
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Mariano Sanz
Facultad de Odontología
Plaza Ramón y Cajal s/n (Ciudad Universitaria)
ES–28040 Madrid (Spain)
E-Mail marianosanz@odon.ucm.es
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... Although the oral cavity was highlighted as a potential reservoir for antibiotic resistance genes several years ago [11][12][13], there is little awareness in the dental community of the potential risks associated with the use of antiseptics with regard to AMR [7,8]. This is notable because a wide range of antiseptics, mostly CHX or the QAC cetylpyridinium chloride (CPC), are included in mouthwashes, gels, or toothpastes that are either intended for professional use in the dental office or available as over-the-counter consumer products [14][15][16][17]. For example, since the COVID-19 pandemic, antiseptics have been routinely used as preprocedural mouthwashes to potentially reduce exposure to SARS-CoV-2 and other microorganisms in dental aerosols [18][19][20]. ...
... The World Health Organization considers free sale of antimicrobial products containing low concentrations of the antimicrobial agent to be a key source of the spread of AMR [40]. In dentistry, antiseptics such as CHX or CPC are used in low concentrations in over-the-counter oral care products such as mouthwashes or toothpastes [7,8,16]. The aim of the present study was to investigate the potential phenotypic adaptation to antiseptics and the development of cross-resistance to antibiotics in oral bacteria upon multiple exposure to subinhibitory concentrations of these antiseptics in vitro. ...
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Despite the wide-spread use of antiseptics in dental practice and oral care products, there is little public awareness of potential risks associated with antiseptic resistance and potentially concomitant cross-resistance. Therefore, the aim of this study was to investigate potential phenotypic adaptation in 177 clinical isolates of early colonizers of dental plaque (Streptococcus, Actinomyces, Rothia and Veillonella spp.) upon repeated exposure to subinhibitory concentrations of chlorhexidine digluconate (CHX) or cetylpyridinium chloride (CPC) over 10 passages using a modified microdilution method. Stability of phenotypic adaptation was re-evaluated after culture in antiseptic-free nutrient broth for 24 or 72 h. Strains showing 8-fold minimal inhibitory concentration (MIC)-increase were further examined regarding their biofilm formation capacity, phenotypic antibiotic resistance and presence of antibiotic resistance genes (ARGs). Eight-fold MIC-increases to CHX were detected in four Streptococcus isolates. These strains mostly exhibited significantly increased biofilm formation capacity compared to their respective wild-type strains. Phenotypic antibiotic resistance was detected to tetracycline and erythromycin, consistent with the detected ARGs. In conclusion, this study shows that clinical isolates of early colonizers of dental plaque can phenotypically adapt toward antiseptics such as CHX upon repeated exposure. The underlying mechanisms at genomic and transcriptomic levels need to be investigated in future studies.
... Chlorhexidine digluconate (CHX), a symmetric bis-biguanide molecule carrying two positive charges, and cetylpyridinium chloride (CPC), a monocationic quaternary ammonium compound (QAC), can be regarded as the most common antiseptics for dental professional use and as ingredients in oral care products (Jones, 1997;Haps et al., 2008;Sanz et al., 2013;van der Weijden et al., 2015;Cieplik et al., 2019a;Mao et al., 2020). While both CHX and CPC are highly effective against planktonic bacteria (Cieplik et al., 2019a;So Yeon and Si Young, 2019;Mao et al., 2020), it is well known that eradicating bacterial cells in biofilms is much more difficult than killing planktonic bacteria and usually requires the antiseptic concentrations of about 100-1,000 times higher than those required to eliminate planktonic bacteria (Ceri et al., 1999;Shani et al., 2000). ...
... Antiseptics are in widespread use in dental practice and also included in numerous over-the-counter oral care products (Haps et al., 2008;Sanz et al., 2013;van der Weijden et al., 2015), but the effects of routine antiseptic use on microbial composition of oral FIGURE 4 | Discriminatory ASVs for biofilms treated with NaCl, CPC, or CHX, respectively, as identified by linear discriminant analysis (LDA) effect size (LEfSe). ASVs exhibiting LDA-score ≥ 4 and adjusted p-values < 0.01 are shown. ...
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Antiseptics are widely used in dental practice and included in numerous over-the-counter oral care products. However, the effects of routine antiseptic use on microbial composition of oral biofilms and on the emergence of resistant phenotypes remain unclear. Microcosm biofilms were inoculated from saliva samples of four donors and cultured in the Amsterdam Active Attachment biofilm model for 3 days. Then, they were treated two times daily with chlorhexidine digluconate (CHX) or cetylpyridinium chloride (CPC) for a period of 7 days. Ecological changes upon these multiple antiseptic treatments were evaluated by semiconductor-based sequencing of bacterial 16S rRNA genes and identification of amplicon sequence variants (ASVs). Furthermore, culture-based approaches were used for colony-forming units (CFU) assay, identification of antiseptic-resistant phenotypes using an agar dilution method, and evaluation of their antibiotic susceptibilities. Both CHX and CPC showed only slight effects on CFU and could not inhibit biofilm growth despite the two times daily treatment for 7 days. Both antiseptics showed significant ecological effects on the microbial compositions of the surviving microbiota, whereby CHX led to enrichment of rather caries-associated saccharolytic taxa and CPC led to enrichment of rather gingivitis-associated proteolytic taxa. Antiseptic-resistant phenotypes were isolated on antiseptic-containing agar plates, which also exhibited phenotypic resistance to various antibiotics. Our results highlight the need for further research into potential detrimental effects of antiseptics on the microbial composition of oral biofilms and on the spread of antimicrobial resistance in the context of their frequent use in oral healthcare.
... Fluoride inhibits enamel demineralization and promotes remineralization by incorporating into apatite crystals, preventing caries formation [8]. Further improvements in plaque and gingivitis reduction can be achieved by brushing with oral hygiene products containing metal actives or quaternary ammonium compounds [9][10][11]. These compounds control the growth and accumulation of bacteria along various oral niches (i.e., teeth, gums, cheeks, and tongue) [12]. ...
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An in situ study was conducted to examine the mode of action of a 0.454% stannous fluoride (SnF2)-containing dentifrice in controlling the composition and properties of oral biofilm. Thirteen generally healthy individuals participated in the study. Each participant wore an intra-oral appliance over a 48-h period to measure differences in the resulting biofilm’s architecture, mechanical properties, and bacterial composition after using two different toothpaste products. In addition, metatranscriptomics analysis of supragingival plaque was conducted to identify the gene pathways influenced. The thickness and volume of the microcolonies formed when brushing with the SnF2 dentifrice were dramatically reduced compared to the control 0.76% sodium monofluorophosphate (MFP)-containing toothpaste. Similarly, the biophysical and nanomechanical properties measured by atomic force microscopy (AFM) demonstrated a significant reduction in biofilm adhesive properties. Metatranscriptomic analysis identified pathways associated with biofilm formation, cell adhesion, quorum sensing, and N-glycosylation that are significantly downregulated with SnF2. This study provides a clinically relevant snapshot of how the use of a stabilized, SnF2 toothpaste formulation can change the spatial organization, nanomechanical, and gene expression properties of bacterial communities.
... The highest antibacterial properties can be reached with chain lengths of C12 to C14 against Gram-positive and C14 to C16 in Gram-negative bacteria, respectively (Huyck, 1945;Maris, 1995). CPC is used as an antimicrobial component in several products/formulation such as dentifrices and mouthwashes to prevent gingivitis and plaque formation (Sanz et al., 2013;Van der Weijden et al., 2015). Its' antimicrobial activity can be significantly increased by combing the CPC with one or more antiseptic compounds (Gilbert and Moore, 2005;Aoun et al., 2015). ...
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... The use of toothpaste can provide a therapeutic effect that may have an antiplaque or anti-inflammatory basis when the nature of the agents is antimicrobial. The antiplaque activity of toothpastes is beneficial for chemical plaque control and thus prevention of dental caries (Sanz et al. 2013). Fluoride and Xylitol are examples of antimicrobial agents which have been incorporated in toothpaste and mouth-rinse preparations to improve the outcome of mechanical oral hygiene procedures (Lippert 2013). ...
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This study investigated the effect of dietary chitosan on growth performances, and carcass traits of sixty-four growing New Zealand White rabbits (NZW). Weaned rabbits were equally distributed among four dietary experimental groups and fed ad libitum for 8 weeks. A basal diet without supplemented chitosan served as a control, the other three groups were fed diet contained 0.2, 0.4 or 0.6 g chitosan/kg diet. Results indicated that, there were significant (P≤0.05) differences among chitosan treatments on productive and carcass traits. Body weight gain was significantly (P≤0.05) increased in group fed 0.2 g chitosan/kg diet compared with other treatments. Also, feed intake significantly (P≤0.05) improved in group fed 0.4 g chitosan/kg compared with other treatments. Moreover, chitosan treatments did not negatively effect on feed consumption during the experimental period. It could be concluded that, using chitosan in 0.2 or 0.4g/kg diet, seemed to be effective to improve rabbit’s body weight gain, and feed conversion ratio under Egyptian conditions.
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Despite the widespread use of antiseptics such as chlorhexidine digluconate (CHX) in dental practice and oral care, the risks of potential resistance toward these antimicrobial compounds in oral bacteria have only been highlighted very recently. Since the molecular mechanisms behind antiseptic resistance or adaptation are not entirely clear and the bacterial stress response has not been investigated systematically so far, the aim of the present study was to investigate the transcriptomic stress response in Streptococcus mutans after treatment with CHX using RNA sequencing (RNA-seq). Planktonic cultures of stationary-phase S. mutans were treated with a sublethal dose of CHX (125 µg/mL) for 5 min. After treatment, RNA was extracted, and RNA-seq was performed on an Illumina NextSeq 500. Differentially expressed genes were analyzed and validated by qRT-PCR. Analysis of differential gene expression following pathway analysis revealed a considerable number of genes and pathways significantly up- or downregulated in S. mutans after sublethal treatment with CHX. In summary, the expression of 404 genes was upregulated, and that of 271 genes was downregulated after sublethal CHX treatment. Analysis of differentially expressed genes and significantly regulated pathways showed regulation of genes involved in purine nucleotide synthesis, biofilm formation, transport systems and stress responses. In conclusion, the results show a transcriptomic stress response in S. mutans upon exposure to CHX and offer insight into potential mechanisms that may result in development of resistances.
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During 2 years of daily use of chlorhexidine mouthrinses 6l students, as well as 59 students using a placebo solution, had determinations of hemoglobin, methemoglobin, sedimentation rate, and numbers of erythrocytes and white cells as well as differential counts. The urine was examined for protein and glucose, and at the end of the experimental period the liver function and kidney function were tested. During the course of the study each participant responded regularly to a general health questionnaire. All the results remained negative, remained within normal range, or returned to normal values. No systemic or local side effect that could be attributed to the use of chlorhexidine was observed.
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Abstract Based on the association of bacterial plaque with the initiation of chronic gingivitis and progression of chronic periodontitis, chemical antiplaque agents have been employed both in prevention of periodontal disease and its treatment. In supragingival plaque control regimens, chlorhexidine has not been superceded as a chemical anti-plaque agent, although other compounds have been shown to be useful. The local side-effects of chlorhexidine and other cationic antiseptics, however, limit their long-term use for prevention. Extrinsic tooth staining in particular remains the greatest problem. Short-term anti-plaque uses for chlorhexidine include (1) as an adjunct to mechanical cleaning in the initial oral hygiene phase of treatment, (2) in situations where mechanical oral hygiene is difficult, including (i) postsurgery. (ii) intermaxillary fixation, (iii) fixed orthodontic therapy, (iv) physically and mentally handicapped individuals, (v) systemic diseases with oral manifestations such as leukaemia. More recent interest in chlorhexidine has resulted from the delivery of compounds subgingivally in the treatment of chronic periodontitis. Such methods have extended the use of chlorhexidine into areas inaccessible to the action of antimicrobial drugs delivered locally by conventional means, such as tooth brushing or mouth rinsing. Available evidence suggests that chlorhexidine may not be as effective as some antimicrobial drugs whose activity is more specific for those organisms considered particularly pathogenic to the periodontal tissues.
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The effects of 0.1% and 0.2% delmopinol mouthwashes on supragingival plaque flora were investigated in a 6-month home-use study. 141 subjects were studied from whom plaque was collected at baseline. 12. 24 and 36 weeks. Overall, there were no consistent effects on microscopic or total counts. However, there was a significant reduction in the proportion of dextran-producing streptococci in the active groups compared to the control group throughout treatment. There was no colonisation by Candida or Gram-negative aerobic bacilli in the active groups nor was there any decrease in susceptibility to delmopinol. Delmopinol appears to mediate its anti-plaque effect without causing a major shift in bacteria! populations, although dextran-producing bacteria appear to be affected, which may have relevance to this agent's mode of action.