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Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial
Accepted Manuscript Title: Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial Author: Carmen Llena Carlos Oteo Jes´us Oteo Jos´e Amengual Leopoldo Forner PII: DOI: Reference:
S0300-5712(15)30029-4 http://dx.doi.org/doi:10.1016/j.jdent.2015.08.004 JJOD 2509
To appear in:
Journal of Dentistry
Received date: Revised date: Accepted date:
5-5-2015 21-7-2015 8-8-2015
Please cite this article as: Llena C, Oteo C, Oteo J, Amengual J, Forner L, Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial, Journal of Dentistry (2015), http://dx.doi.org/10.1016/j.jdent.2015.08.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial. Carmen Llena. MD, DDS, PhD Universitat de València (Valencia, Spain). Clínica Odontológica. C. Gascó Oliag, 1. 46010 Valencia. Spain.
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Carlos Oteo. MD, DDS, PhD Universidad Complutense de Madrid (Madrid, Spain). Facultad de Odontología. Plaza Ramón y Cajal, 3. Ciudad Universitaria. 28040 Madrid. Spain.
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Jesús Oteo. MD, DDS, PhD Universidad Complutense de Madrid (Madrid, Spain). Facultad de Odontología. Plaza Ramón y Cajal, 3. Ciudad Universitaria. 28040 Madrid. Spain.
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José Amengual. MD, DDS, PhD Universitat de València (Valencia, Spain). Clínica Odontológica. C. Gascó Oliag, 1. 46010 Valencia. Spain.
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Corresponding author: Carmen Llena [email protected] Phone: +34 963864175 Fax: +34 963864144
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Leopoldo Forner. MD, DDS, PhD Universitat de València (Valencia, Spain). Clínica Odontológica. C. Gascó Oliag, 1. 46010 Valencia. Spain.
Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial. ABSTRACT.
Objectives. To assess the efficacy of a bleaching enzyme-based toothpaste. Material and methods. A randomized clinical trial was carried out, comprising 48 participants with teeth exhibiting color A3 or higher according to the Vita Classical guide. One-half of the sample received the bleaching enzyme-based toothpaste (White Kin®), while the other received placebo toothpaste. Both products were supplied in identical containers and had the same composition except for the active components. The teeth color was measured with a spectrophotometer. The patients were instructed to brush their teeth three times a day during three minutes with the assigned product, during 12 weeks. The color measurements were repeated after 3, 1
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6, 9 and 12 weeks of treatment. Color variation was based on the CIE L*a*b* coordinates, ∆E and the EW index. The relationship of these variables at different observation times were performed using a generalized estimating equations model, which evaluated the effect of treatment, time and interaction. Results. The patients using the bleaching enzyme-based toothpaste showed an increase in lightness (80.14 treatment- vs. 79.25 -control group-) and a reduction in component b*. ∆E was found higher in the treatment group (p = 0.064), close to statistical significance. Conclusions. The bleaching enzyme-based toothpaste could be potentially efficient in the modification in tooth
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color progressing from the third to ninth week of treatment, tending to stabilize after the ninth week
Clinical relevance. A very low carbamide peroxide concentration, with the incorporation of lactoperoxidase, tooth paste, tends to offer clinically satisfactory results, in terms of modifications in tooth color, nevertheless no
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significant differences were founded when compared to the control group, with an oral hygiene controlled along
KEY WORDS.
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Tooth bleaching, carbamide peroxide, lactoperoxidase, toothpaste.
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the study.
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Introduction Dental bleaching is a very popular conservative option for the treatment of dental discoloration 1. Hydrogen peroxide (HP) and its precursor, carbamide peroxide (CP), are presently in the active agents most widely used both in dental clinics and at home 2. These two bleaching substances can maintain their effects over the middle and long term, and are well tolerated by the oral tissues 3. In recent years, systems with different peroxide concentrations and involving different application effective, easy to use and well tolerated by the oral tissues 4.
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methods and activation mechanisms have been developed with the purpose of offering products that are
One of the aims of research in dental bleaching is to define activation mechanisms capable of affording 5-7
. Such activation mechanisms include
the use of physical agents (particularly different light sources), chemicals
8-11
and enzymes 5. In this context,
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optimum free radical action with the lowest HP concentration possible
enzymatic bleaching involving the use of enzymes such as catalase, oxidoreductases and peroxidases, acts by 12-14
. Salivary peroxidase intervenes in the transformation of HP into a
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increasing the HP decomposition rate
harmless substance. This effect constituted the basis for the inclusion of this enzyme in the composition of dental bleaching products 7, 15-17.
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It has been shown that lactoperoxidase (LP) can be employed to catalyze peroxide decomposition, and its stability makes it usable in gel formulations5. A bleaching toothpaste (White Kin® Bleaching System, Laboratorios KIN, Barcelona, Spain) containing this enzyme has been developed. This product contains 3% the risk of undesirable effects 5, 17.
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carbamide peroxide and 5% lactoperoxidase, with the purpose of reducing the peroxide concentration and thus
A previous clinical study carried out by our group in volunteers using this bleaching enzyme-based
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toothpaste recorded a significant improvement in tooth color after 21 days of treatment (3 daily applications) 6.
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The present clinical trial was designed to test the following null hypothesis: the enzymatically activated bleaching toothpaste (White Kin®) has the same bleaching efficacy as a placebo formulation when used during 12 weeks.
The objective was to evaluate the efficacy of a bleaching product based on 3% carbamide peroxide and
5% lactoperoxidase, used during 12 weeks, and to compare it with a placebo formulation.
Materials and Methods
Sample selection and criteria, randomization and blinding The present study was approved by the Ethics Committee of San Carlos Clinic Hospital (Madrid
Complutense University, Madrid, Spain) (CP-CI 10/355-E). A two-center randomized clinical trial (RCT) was carried out (universal trial number: U111-1154-9986) in the Dental Clinic of the Lluís Alcanyís Foundation of the University of Valencia (Valencia, Spain) and in the Dental Clinic of Madrid Complutense University (Madrid, Spain). Each center enrolled 24 participants between 18-60 years of age (Figure 1). 3
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The primary study outcome was color change evaluated by ∆E. This therefore was the variable used for the determination of sample size. Considering patient as an experimental unit, the sample size was calculated to obtain a ∆E difference at the end of the study of 1 unit between both groups, with a statistical power of 80%, and a significance level of 5%. The resulting sample size was 21 patients by group. Assuming a loss of 15% in the course of the study, the final sample size was defined as 24 participants per group. The inclusion criteria were: patients between 18-60 years of age, with fully erupted upper and lower incisors and canines without dental or periodontal disease or restorations, and with at least one maxillary tooth
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presenting color score A3 or darker, as measured with the Vita Classical guide (Vita Zahnfabrik, Bad Säckingen, Germany) ordered by brightness19. The exclusion criteria were: patients with systemic diseases or oral mucosal
with known allergy to the product ingredients, smokers, and alcohol abusers.
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disorders, previous bleaching treatment, patients undergoing orthodontic treatment, pregnant women, people
The treatment product was the White Kin® Bleaching System gel + toothpaste (Laboratorios KIN,
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Barcelona, Spain), supplied in the form of two tubes, each with an independent dosifier allowing administration of the contents in equal portions. One tube contained toothpaste with 5% LP, together with other ingredients (sodium fluoride, xylitol and excipients), while the other contained a gel with 3% CP and excipients.
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The placebo was supplied by the same company (Laboratorios Kin, Barcelona, Spain) in the form of two tubes, each with an independent dosifier identical to that of the active product. The toothpaste in this case
same ingredients as the active gel, but without CP.
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had the same composition as in the treatment group, but without LP. The tube with the gel in turn contained the
The containers were numbered by an independent researcher from 1 to 48, and 24 containers were randomly assigned to each participating clinic using a computer-generated list of random numbers. As a result,
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neither the investigators nor the participants knew which treatment (active product or placebo) was being used
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(double-blind study design). In each center the 24 containers were successively assigned to each of the participants upon entering the study. Procedure
Professional plaque elimination was carried out in all patients using ultrasound instruments followed by
polishing with a fluoride-free prophylactic paste.
Casts of the arches were obtained for the preparation of splints designed in order to always measure
tooth color in the same location 20. Circular perforations measuring 6 mm in diameter (coinciding with that of the spectrophotometer tip) were made in the splints. The tip of the instrument was inserted in the perforation to directly measure the color on the tooth surface, and always in the same position. Tooth color of maxillary and mandibular incisors and canines was evaluated at baseline and again after
3, 6, 9 and 12 weeks, using a spectrophotometer (Vita Easy Shade, Vita Zahnfabrik, Bad Säckingen, Germany). A single investigator in each clinic recorded the color in all the patients, at each of the study timepoints. Both investigators were previously calibrated by means of a sample of 10 patients with the same characteristics as the study subjects, using an individualized plastic color recording guide identical to that used in the study. The Intraclass Correlation Coefficient (ICC) between the two investigators in determining the coordinates L*, a* and b* provided by the spectrophotometer was R=0.98, R=0.96 and R=0.97, respectively. In the course of the study, 4
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each center repeated the determinations of three patients at each of the study timepoints in order to check the internal consistency of each investigator (we recorded an ICC>0.9 for both investigators in all cases). The color was established according to the CIE L*a*b* spatial coordinates L*, a*, b* 21, and always in the same central zone of the tooth. Based on the variables L*, a*, b*, we calculated the following indices: ∆Ε at each study timepoint with respect to baseline, and the EW index or distance of a color from pure white (L*=100, a*=0 and b*=0). This index was measured at baseline and at each of the study time points 22. An identifying number was assigned to each participant, and each subject received four containers of
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product (enough for 12 weeks of use), labeled with a number, together with a toothbrush (FKD Adult Toothbrush, Laboratorios KIN, Barcelona, Spain). Likewise, written instructions were provided on how to use and store the product, along with the treatment protocol (three brushings a day for three minutes during 12
added food colorants (tea, coffee, red wine, red fruits, tomato sauce, etc.).
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weeks). The patients were also instructed to avoid food and drink capable of producing coloring effects, or with
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In the course of the study, one participant declined to continue participating due to personal reasons, and was excluded from the statistical analysis (Figure 1).
For comparisons between the active treatment group and the control (placebo) series, the investigator in
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charge of the statistical analysis was informed of the tube numbers corresponding to placebo and those corresponding to the active treatment product.
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Statistical analysis
Data were analyzed using SPSS for Windows softwear, version 19 (IBM Co., Chicago, Il, USA). Concordance between both operators and the consistency of each one of them to assess L*, a* and b*
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measurements along the study, was calculated through the ICC.
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The response variables of the study were L*, a*, b*, EW and ∆E, which were evaluated at different moments during the study (baseline, 3, 6, 9 and 12 weeks). The average values of each variable from each patient were assessed, using the “patient” as the unit of
analysis. When a normal distribution in both groups were assessed through the Kolmogorov-Smirnov test, T test was used to do a comparison between both groups. Levene test was used to assess homogeneity of variances. Significant level was set up at 5% (p=0.05).
Results
45 patients were analyzed, 22 of which corresponded to the control group and 23 to the treatment group.
One patient from the control group decline to complete the study for personal reasons, then, he was excluded from the analysis. The mean patient age was 29 ± 4 years, 74.8% were females. During the treatment period, none of the subjects reported dental hypersensitivity, discomfort of the gums or oral mucosa, or any other deleterious effects. The effect of the treatment over the ∆E showed a 12 week p value = 0.064 (table 1), pointing an improvement in close to the significant value in this group. Table 1 shows descriptive values for ∆E along the 5
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study period for each group. Differences were the highest, but not significant, at 3 and 6 weeks (p= 0.061 and p=0.448, respectively). We did not found a significant brightness, a* b* or EW variations between both groups along the study (p=0.673, p=0.779, p= 0.835, p=0.723), as can be seen in table 2, but absolute values showed a brightness increase (79.25 vs 80.14) and a reduction of the b* component (20.60 vs 20.19) in the treatment group at the end of the follow-up period. EW was closer to pure white in the treatment group, but without significant differences when compared to control group (p=0.723). Descriptive data for these parameters, between the beginning and
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the end of the study, are shown in table 2.
Discussion
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The Vita Classical guide was used for patient inclusion in the study, since it is the most widely used instrument for recording color, and allows faster patient screening. We included participants with a color score
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of A3 or higher for some maxillary tooth, in accordance with the recommendations of Zantner et al. in 2006 19. The changes in color and spectral distribution were measured according to the CIE L*a*b* system using a spectrophotometer (Vita Easy Shade, Vita Zahnfabrik, Bad Säckingen, Germany), since this is an
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objective procedure that allows transformation of the visual impression into numerical coordinates that can be compared by mathematical methods 23. However, an inconvenience of this technique is the poor reproducibility of the registries, since different measurements can be obtained from one same tooth depending on the location of
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the tip of the apparatus on the dental surface. For this reason, and in order to measure color always in the same area of the tooth, we prepared splints with circular perforations of a diameter coinciding with that of the spectrophotometer tip. The latter was inserted in the perforation to directly measure the color on the tooth
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surface, and always in the same position 24,25.
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Despite the benefits of the objective measurement of tooth color in dentistry, there are some limitations. In this sense, some authors such as Gonzalo-Diaz
26
have warned of the possible color discrepancies which
clinical-use color screening instruments can produce because of the “lost background effect” of translucent materials when both illumination and the light reflected by the object follow the same trajectory within a narrow recording device. In order to avoid this effect, some authors recommend using an external light source that produces no shadows and a spectroradiometer
26-28
. However, the clinical use of this procedure is very limited,
since the reflectance standards used are flat and opaque – not curved, textured and translucent like dental tissues 29,30
. It is important to emphasize that the teeth and gums are not flat but have texture and are composed of
tissues that experience color transitions depending on the area studied. Thus, despite the lack of a reference instrument for clinical use in validating scientific studies, spectrophotometers are cited by the literature as the best option for obtaining precise and repeatable measurements 31-34. Although there is not enough statistical evidence to reject the null hypothesis, the data are indicative of a trend in favor of treatment group. Color variations were evaluated based on the ∆E, which reflects clearing of the tooth color
35,36
. In this
context, it is accepted that variations in ∆E of ≥ 2 units reflect color changes, while variations of ≥ 2.6 units are indicative of clinically manifest changes in tooth color 18. In our study, the treatment group showed ∆E values of 6
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> 4 units. In the control group we also recorded improvements in tooth color based on the ∆E values. These variations may have been due to the effect of the placebo toothpaste itself, and to more thorough dental cleaning on the part of the patients attributable to the fact that they were aware of their participation in a clinical trial (the so-called Hawthorne effect) 19. We must take in account that each participant in the study came each 3 weeks to the clinic with their toothbrush and toothpaste, there, we controlled the amount of toothpaste used during the period evaluated and we reinforced patient motivation and we remembered them how the procedure should be done (frequency, duration, and technique). Placebo paste did not contain any specific agent with antiplaque, anti-
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tartar, or bleaching activity, while the treatment paste contained 3% carbamide peroxide and 5% lactoperoxidase, The excipient of both pastes contained silica. Lower values of the whitening index or EW
22
indicate a tooth color closer to pure white. In our study,
way, a tendency towards white (0.45 units) was detected in the treatment group.
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there were no significant differences between both groups at the end of the study, nevertheless, in a descriptive
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To our knowledge, no other clinical trials have evaluated the toothpaste used in our study. The studies made with bleaching toothpastes or oral rinses containing peroxides at low concentrations offer contradictory results. Two studies that compared toothpastes and rinses containing hydrogen peroxide at concentrations
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between 1-2% reported no improvements in tooth color after 1-2 weeks of treatment 37,38. In contrast, an in vitro study with 1.5% and 2% hydrogen peroxide rinses versus a control toothpaste, simulating clinical conditions, recorded significantly higher ∆E values in the active treatment groups, and similar to those obtained with a 10%
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carbamide peroxide gel39. Other in vivo studies involving different toothpastes with a hydrogen peroxide concentration in the range of 1% reported improvements in tooth color, with values similar to those obtained in our study
40-42
. The 3% carbamide peroxide formulation used in our study is equivalent to a hydrogen peroxide
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concentration of 1.08%, i.e., similar to the concentrations used in the aforementioned publications. The 37,38
and the rest of the commented publications may
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discrepancy between the results reported by Gerlach et al.
be attributable to the short follow-up involved (1-2 weeks) compared with the other studies in which follow-up lasted 6-12 weeks.
A previous clinical study with this same product 6 revealed improvement of the color of the treated teeth
when applied for three weeks, with a likewise significant increase in brightness at the end of treatment. In our study we contemplated a longer duration in order to determine whether increased improvements are obtained by prolonging treatment. In this regard, we found that brightness increases and component b* decreased but without significant differences through the study period.
∆E was higher at every time studied along the follow-up period in the treatment group, close to the
significant values at 3 and 12 weeks. Table 1 shows how ∆E grows up along the study with a tendency to stability from the ninth week, suggesting that the period to get an effective result with the analyzed bleaching toothpaste could be assessed around 9 weeks. There are concerns about the possible pathological effects of relatively long-term exposure of oral tissues to bleaching agents. Laboratory studies have shown bleaching agents which generate approximately 3% hydrogen peroxide to be toxic for human gingival fibroblasts. However, such toxicity is neutralized with the addition of catalase or lactoperoxidase to the cultures
17,43
. Lactoperoxidase, when added in a toothpaste for 7
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prolonged use, can provide protection for the oral soft tissues, effect that is not found in other whitening toothpastes. In addition, low-level doses of bleaching agents avoid undesirable effects 44,45. Studies on the effects of long-term bleaching treatments describe partial loss of the results obtained 6 months after the end of treatment, in approximately one-half of the cases
46,47
. Similar behavior might also be
expected from the product evaluated in our study, though such studies are not presently available. On the other hand, the characteristics of the studied toothpaste (with a very low hydrogen peroxide concentration plus an enzyme) suggest that it could be used for prolonged periods of treatment, with minimization of the loss of effect.
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Likewise, the evaluated product could be recommended as maintenance treatment after bleaching performed with higher concentration products, again with the purpose of delaying discoloration relapse.
It can be concluded that, although in the treatment group clearance was not significantly higher than in
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the control group, the data are indicative of a trend toward a higher one in the treatment group
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Ethical statements
This study was approved by the Ethics Committee of San Carlos Clinic Hospital (Madrid Complutense University, Madrid, Spain) (registry number: 10/335-E), and was conducted in accordance to the ethical
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standards laid down in the 1964 Declaration of Helsinki and its later amendments.
A written and verbal explanation was given of the study objectives, the possible side effects, and of the
informed consent document.
Suport
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importance of complying with normal dental hygiene. All participants in the study signed the corresponding
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Laboratorios Kin (Barcelona –Spain-) provided treatment and placebo toothpastes.
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Figure captions
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Fig. 1. Flowchart of the trial.
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fig 1.jpg
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Table 1. Mean and standard deviation (SD) for the ∆E value of all bleached teeth for both groups at 3, 6, 9 and 12 weeks follow-up.
3 weeks p =0.061
mean 3.13 3.89
SD 1.36 1.07
Control Treatment
6 weeks p =0.448
3.25 4.02
1.62 1.89
Control Treatment
9 weeks p =0.114
3.61 4.19
1.35 1.77
Control Treatment
12 weeks p =0.064
3.83 4.23
1.13 1.57
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Control Treatment
Table 2. Mean and SD L*a*b* EW values of all bleached teeth for both groups at baseline and 12 weeks follow up.
L* Baseline
Control
mean 79.76
SD 3.63 12
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3.61 3.93 3.41
Control Treatment Control Treatment
-0.88 -0.67 -0.84 -0.77
0.09 0.08 0.09 0.08
Control Treatment Control Treatment
20.70 20.65 20.60 20.19
3.57 3.67 4.01 2.74
Control Treatment Control Treatment
29.39 29.15 29.13 28.68.
3.73 3.80 3.78 3.46
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79.86 79.25 80.14
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a* Baseline p=0.452 12 weeks p=0.779 b* Baseline p=0.835 12 weeks p=0.133 EW Baseline p=0.738 12 weeks p=0.723
Treatment Control Treatment
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12 weeks p=0.673
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S0300-5712(15)30029-4 http://dx.doi.org/doi:10.1016/j.jdent.2015.08.004 JJOD 2509
To appear in:
Journal of Dentistry
Received date: Revised date: Accepted date:
5-5-2015 21-7-2015 8-8-2015
Please cite this article as: Llena C, Oteo C, Oteo J, Amengual J, Forner L, Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial, Journal of Dentistry (2015), http://dx.doi.org/10.1016/j.jdent.2015.08.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial. Carmen Llena. MD, DDS, PhD Universitat de València (Valencia, Spain). Clínica Odontológica. C. Gascó Oliag, 1. 46010 Valencia. Spain.
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Carlos Oteo. MD, DDS, PhD Universidad Complutense de Madrid (Madrid, Spain). Facultad de Odontología. Plaza Ramón y Cajal, 3. Ciudad Universitaria. 28040 Madrid. Spain.
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Jesús Oteo. MD, DDS, PhD Universidad Complutense de Madrid (Madrid, Spain). Facultad de Odontología. Plaza Ramón y Cajal, 3. Ciudad Universitaria. 28040 Madrid. Spain.
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José Amengual. MD, DDS, PhD Universitat de València (Valencia, Spain). Clínica Odontológica. C. Gascó Oliag, 1. 46010 Valencia. Spain.
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Corresponding author: Carmen Llena [email protected] Phone: +34 963864175 Fax: +34 963864144
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Leopoldo Forner. MD, DDS, PhD Universitat de València (Valencia, Spain). Clínica Odontológica. C. Gascó Oliag, 1. 46010 Valencia. Spain.
Clinical efficacy of a bleaching enzyme-based toothpaste. A double-blind controlled clinical trial. ABSTRACT.
Objectives. To assess the efficacy of a bleaching enzyme-based toothpaste. Material and methods. A randomized clinical trial was carried out, comprising 48 participants with teeth exhibiting color A3 or higher according to the Vita Classical guide. One-half of the sample received the bleaching enzyme-based toothpaste (White Kin®), while the other received placebo toothpaste. Both products were supplied in identical containers and had the same composition except for the active components. The teeth color was measured with a spectrophotometer. The patients were instructed to brush their teeth three times a day during three minutes with the assigned product, during 12 weeks. The color measurements were repeated after 3, 1
Page 1 of 13
6, 9 and 12 weeks of treatment. Color variation was based on the CIE L*a*b* coordinates, ∆E and the EW index. The relationship of these variables at different observation times were performed using a generalized estimating equations model, which evaluated the effect of treatment, time and interaction. Results. The patients using the bleaching enzyme-based toothpaste showed an increase in lightness (80.14 treatment- vs. 79.25 -control group-) and a reduction in component b*. ∆E was found higher in the treatment group (p = 0.064), close to statistical significance. Conclusions. The bleaching enzyme-based toothpaste could be potentially efficient in the modification in tooth
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color progressing from the third to ninth week of treatment, tending to stabilize after the ninth week
Clinical relevance. A very low carbamide peroxide concentration, with the incorporation of lactoperoxidase, tooth paste, tends to offer clinically satisfactory results, in terms of modifications in tooth color, nevertheless no
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significant differences were founded when compared to the control group, with an oral hygiene controlled along
KEY WORDS.
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Tooth bleaching, carbamide peroxide, lactoperoxidase, toothpaste.
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the study.
2
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Introduction Dental bleaching is a very popular conservative option for the treatment of dental discoloration 1. Hydrogen peroxide (HP) and its precursor, carbamide peroxide (CP), are presently in the active agents most widely used both in dental clinics and at home 2. These two bleaching substances can maintain their effects over the middle and long term, and are well tolerated by the oral tissues 3. In recent years, systems with different peroxide concentrations and involving different application effective, easy to use and well tolerated by the oral tissues 4.
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methods and activation mechanisms have been developed with the purpose of offering products that are
One of the aims of research in dental bleaching is to define activation mechanisms capable of affording 5-7
. Such activation mechanisms include
the use of physical agents (particularly different light sources), chemicals
8-11
and enzymes 5. In this context,
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optimum free radical action with the lowest HP concentration possible
enzymatic bleaching involving the use of enzymes such as catalase, oxidoreductases and peroxidases, acts by 12-14
. Salivary peroxidase intervenes in the transformation of HP into a
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increasing the HP decomposition rate
harmless substance. This effect constituted the basis for the inclusion of this enzyme in the composition of dental bleaching products 7, 15-17.
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It has been shown that lactoperoxidase (LP) can be employed to catalyze peroxide decomposition, and its stability makes it usable in gel formulations5. A bleaching toothpaste (White Kin® Bleaching System, Laboratorios KIN, Barcelona, Spain) containing this enzyme has been developed. This product contains 3% the risk of undesirable effects 5, 17.
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carbamide peroxide and 5% lactoperoxidase, with the purpose of reducing the peroxide concentration and thus
A previous clinical study carried out by our group in volunteers using this bleaching enzyme-based
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toothpaste recorded a significant improvement in tooth color after 21 days of treatment (3 daily applications) 6.
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The present clinical trial was designed to test the following null hypothesis: the enzymatically activated bleaching toothpaste (White Kin®) has the same bleaching efficacy as a placebo formulation when used during 12 weeks.
The objective was to evaluate the efficacy of a bleaching product based on 3% carbamide peroxide and
5% lactoperoxidase, used during 12 weeks, and to compare it with a placebo formulation.
Materials and Methods
Sample selection and criteria, randomization and blinding The present study was approved by the Ethics Committee of San Carlos Clinic Hospital (Madrid
Complutense University, Madrid, Spain) (CP-CI 10/355-E). A two-center randomized clinical trial (RCT) was carried out (universal trial number: U111-1154-9986) in the Dental Clinic of the Lluís Alcanyís Foundation of the University of Valencia (Valencia, Spain) and in the Dental Clinic of Madrid Complutense University (Madrid, Spain). Each center enrolled 24 participants between 18-60 years of age (Figure 1). 3
Page 3 of 13
The primary study outcome was color change evaluated by ∆E. This therefore was the variable used for the determination of sample size. Considering patient as an experimental unit, the sample size was calculated to obtain a ∆E difference at the end of the study of 1 unit between both groups, with a statistical power of 80%, and a significance level of 5%. The resulting sample size was 21 patients by group. Assuming a loss of 15% in the course of the study, the final sample size was defined as 24 participants per group. The inclusion criteria were: patients between 18-60 years of age, with fully erupted upper and lower incisors and canines without dental or periodontal disease or restorations, and with at least one maxillary tooth
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presenting color score A3 or darker, as measured with the Vita Classical guide (Vita Zahnfabrik, Bad Säckingen, Germany) ordered by brightness19. The exclusion criteria were: patients with systemic diseases or oral mucosal
with known allergy to the product ingredients, smokers, and alcohol abusers.
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disorders, previous bleaching treatment, patients undergoing orthodontic treatment, pregnant women, people
The treatment product was the White Kin® Bleaching System gel + toothpaste (Laboratorios KIN,
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Barcelona, Spain), supplied in the form of two tubes, each with an independent dosifier allowing administration of the contents in equal portions. One tube contained toothpaste with 5% LP, together with other ingredients (sodium fluoride, xylitol and excipients), while the other contained a gel with 3% CP and excipients.
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The placebo was supplied by the same company (Laboratorios Kin, Barcelona, Spain) in the form of two tubes, each with an independent dosifier identical to that of the active product. The toothpaste in this case
same ingredients as the active gel, but without CP.
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had the same composition as in the treatment group, but without LP. The tube with the gel in turn contained the
The containers were numbered by an independent researcher from 1 to 48, and 24 containers were randomly assigned to each participating clinic using a computer-generated list of random numbers. As a result,
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neither the investigators nor the participants knew which treatment (active product or placebo) was being used
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(double-blind study design). In each center the 24 containers were successively assigned to each of the participants upon entering the study. Procedure
Professional plaque elimination was carried out in all patients using ultrasound instruments followed by
polishing with a fluoride-free prophylactic paste.
Casts of the arches were obtained for the preparation of splints designed in order to always measure
tooth color in the same location 20. Circular perforations measuring 6 mm in diameter (coinciding with that of the spectrophotometer tip) were made in the splints. The tip of the instrument was inserted in the perforation to directly measure the color on the tooth surface, and always in the same position. Tooth color of maxillary and mandibular incisors and canines was evaluated at baseline and again after
3, 6, 9 and 12 weeks, using a spectrophotometer (Vita Easy Shade, Vita Zahnfabrik, Bad Säckingen, Germany). A single investigator in each clinic recorded the color in all the patients, at each of the study timepoints. Both investigators were previously calibrated by means of a sample of 10 patients with the same characteristics as the study subjects, using an individualized plastic color recording guide identical to that used in the study. The Intraclass Correlation Coefficient (ICC) between the two investigators in determining the coordinates L*, a* and b* provided by the spectrophotometer was R=0.98, R=0.96 and R=0.97, respectively. In the course of the study, 4
Page 4 of 13
each center repeated the determinations of three patients at each of the study timepoints in order to check the internal consistency of each investigator (we recorded an ICC>0.9 for both investigators in all cases). The color was established according to the CIE L*a*b* spatial coordinates L*, a*, b* 21, and always in the same central zone of the tooth. Based on the variables L*, a*, b*, we calculated the following indices: ∆Ε at each study timepoint with respect to baseline, and the EW index or distance of a color from pure white (L*=100, a*=0 and b*=0). This index was measured at baseline and at each of the study time points 22. An identifying number was assigned to each participant, and each subject received four containers of
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product (enough for 12 weeks of use), labeled with a number, together with a toothbrush (FKD Adult Toothbrush, Laboratorios KIN, Barcelona, Spain). Likewise, written instructions were provided on how to use and store the product, along with the treatment protocol (three brushings a day for three minutes during 12
added food colorants (tea, coffee, red wine, red fruits, tomato sauce, etc.).
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weeks). The patients were also instructed to avoid food and drink capable of producing coloring effects, or with
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In the course of the study, one participant declined to continue participating due to personal reasons, and was excluded from the statistical analysis (Figure 1).
For comparisons between the active treatment group and the control (placebo) series, the investigator in
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charge of the statistical analysis was informed of the tube numbers corresponding to placebo and those corresponding to the active treatment product.
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Statistical analysis
Data were analyzed using SPSS for Windows softwear, version 19 (IBM Co., Chicago, Il, USA). Concordance between both operators and the consistency of each one of them to assess L*, a* and b*
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measurements along the study, was calculated through the ICC.
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The response variables of the study were L*, a*, b*, EW and ∆E, which were evaluated at different moments during the study (baseline, 3, 6, 9 and 12 weeks). The average values of each variable from each patient were assessed, using the “patient” as the unit of
analysis. When a normal distribution in both groups were assessed through the Kolmogorov-Smirnov test, T test was used to do a comparison between both groups. Levene test was used to assess homogeneity of variances. Significant level was set up at 5% (p=0.05).
Results
45 patients were analyzed, 22 of which corresponded to the control group and 23 to the treatment group.
One patient from the control group decline to complete the study for personal reasons, then, he was excluded from the analysis. The mean patient age was 29 ± 4 years, 74.8% were females. During the treatment period, none of the subjects reported dental hypersensitivity, discomfort of the gums or oral mucosa, or any other deleterious effects. The effect of the treatment over the ∆E showed a 12 week p value = 0.064 (table 1), pointing an improvement in close to the significant value in this group. Table 1 shows descriptive values for ∆E along the 5
Page 5 of 13
study period for each group. Differences were the highest, but not significant, at 3 and 6 weeks (p= 0.061 and p=0.448, respectively). We did not found a significant brightness, a* b* or EW variations between both groups along the study (p=0.673, p=0.779, p= 0.835, p=0.723), as can be seen in table 2, but absolute values showed a brightness increase (79.25 vs 80.14) and a reduction of the b* component (20.60 vs 20.19) in the treatment group at the end of the follow-up period. EW was closer to pure white in the treatment group, but without significant differences when compared to control group (p=0.723). Descriptive data for these parameters, between the beginning and
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the end of the study, are shown in table 2.
Discussion
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The Vita Classical guide was used for patient inclusion in the study, since it is the most widely used instrument for recording color, and allows faster patient screening. We included participants with a color score
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of A3 or higher for some maxillary tooth, in accordance with the recommendations of Zantner et al. in 2006 19. The changes in color and spectral distribution were measured according to the CIE L*a*b* system using a spectrophotometer (Vita Easy Shade, Vita Zahnfabrik, Bad Säckingen, Germany), since this is an
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objective procedure that allows transformation of the visual impression into numerical coordinates that can be compared by mathematical methods 23. However, an inconvenience of this technique is the poor reproducibility of the registries, since different measurements can be obtained from one same tooth depending on the location of
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the tip of the apparatus on the dental surface. For this reason, and in order to measure color always in the same area of the tooth, we prepared splints with circular perforations of a diameter coinciding with that of the spectrophotometer tip. The latter was inserted in the perforation to directly measure the color on the tooth
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surface, and always in the same position 24,25.
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Despite the benefits of the objective measurement of tooth color in dentistry, there are some limitations. In this sense, some authors such as Gonzalo-Diaz
26
have warned of the possible color discrepancies which
clinical-use color screening instruments can produce because of the “lost background effect” of translucent materials when both illumination and the light reflected by the object follow the same trajectory within a narrow recording device. In order to avoid this effect, some authors recommend using an external light source that produces no shadows and a spectroradiometer
26-28
. However, the clinical use of this procedure is very limited,
since the reflectance standards used are flat and opaque – not curved, textured and translucent like dental tissues 29,30
. It is important to emphasize that the teeth and gums are not flat but have texture and are composed of
tissues that experience color transitions depending on the area studied. Thus, despite the lack of a reference instrument for clinical use in validating scientific studies, spectrophotometers are cited by the literature as the best option for obtaining precise and repeatable measurements 31-34. Although there is not enough statistical evidence to reject the null hypothesis, the data are indicative of a trend in favor of treatment group. Color variations were evaluated based on the ∆E, which reflects clearing of the tooth color
35,36
. In this
context, it is accepted that variations in ∆E of ≥ 2 units reflect color changes, while variations of ≥ 2.6 units are indicative of clinically manifest changes in tooth color 18. In our study, the treatment group showed ∆E values of 6
Page 6 of 13
> 4 units. In the control group we also recorded improvements in tooth color based on the ∆E values. These variations may have been due to the effect of the placebo toothpaste itself, and to more thorough dental cleaning on the part of the patients attributable to the fact that they were aware of their participation in a clinical trial (the so-called Hawthorne effect) 19. We must take in account that each participant in the study came each 3 weeks to the clinic with their toothbrush and toothpaste, there, we controlled the amount of toothpaste used during the period evaluated and we reinforced patient motivation and we remembered them how the procedure should be done (frequency, duration, and technique). Placebo paste did not contain any specific agent with antiplaque, anti-
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tartar, or bleaching activity, while the treatment paste contained 3% carbamide peroxide and 5% lactoperoxidase, The excipient of both pastes contained silica. Lower values of the whitening index or EW
22
indicate a tooth color closer to pure white. In our study,
way, a tendency towards white (0.45 units) was detected in the treatment group.
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there were no significant differences between both groups at the end of the study, nevertheless, in a descriptive
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To our knowledge, no other clinical trials have evaluated the toothpaste used in our study. The studies made with bleaching toothpastes or oral rinses containing peroxides at low concentrations offer contradictory results. Two studies that compared toothpastes and rinses containing hydrogen peroxide at concentrations
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between 1-2% reported no improvements in tooth color after 1-2 weeks of treatment 37,38. In contrast, an in vitro study with 1.5% and 2% hydrogen peroxide rinses versus a control toothpaste, simulating clinical conditions, recorded significantly higher ∆E values in the active treatment groups, and similar to those obtained with a 10%
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carbamide peroxide gel39. Other in vivo studies involving different toothpastes with a hydrogen peroxide concentration in the range of 1% reported improvements in tooth color, with values similar to those obtained in our study
40-42
. The 3% carbamide peroxide formulation used in our study is equivalent to a hydrogen peroxide
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concentration of 1.08%, i.e., similar to the concentrations used in the aforementioned publications. The 37,38
and the rest of the commented publications may
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discrepancy between the results reported by Gerlach et al.
be attributable to the short follow-up involved (1-2 weeks) compared with the other studies in which follow-up lasted 6-12 weeks.
A previous clinical study with this same product 6 revealed improvement of the color of the treated teeth
when applied for three weeks, with a likewise significant increase in brightness at the end of treatment. In our study we contemplated a longer duration in order to determine whether increased improvements are obtained by prolonging treatment. In this regard, we found that brightness increases and component b* decreased but without significant differences through the study period.
∆E was higher at every time studied along the follow-up period in the treatment group, close to the
significant values at 3 and 12 weeks. Table 1 shows how ∆E grows up along the study with a tendency to stability from the ninth week, suggesting that the period to get an effective result with the analyzed bleaching toothpaste could be assessed around 9 weeks. There are concerns about the possible pathological effects of relatively long-term exposure of oral tissues to bleaching agents. Laboratory studies have shown bleaching agents which generate approximately 3% hydrogen peroxide to be toxic for human gingival fibroblasts. However, such toxicity is neutralized with the addition of catalase or lactoperoxidase to the cultures
17,43
. Lactoperoxidase, when added in a toothpaste for 7
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prolonged use, can provide protection for the oral soft tissues, effect that is not found in other whitening toothpastes. In addition, low-level doses of bleaching agents avoid undesirable effects 44,45. Studies on the effects of long-term bleaching treatments describe partial loss of the results obtained 6 months after the end of treatment, in approximately one-half of the cases
46,47
. Similar behavior might also be
expected from the product evaluated in our study, though such studies are not presently available. On the other hand, the characteristics of the studied toothpaste (with a very low hydrogen peroxide concentration plus an enzyme) suggest that it could be used for prolonged periods of treatment, with minimization of the loss of effect.
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Likewise, the evaluated product could be recommended as maintenance treatment after bleaching performed with higher concentration products, again with the purpose of delaying discoloration relapse.
It can be concluded that, although in the treatment group clearance was not significantly higher than in
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the control group, the data are indicative of a trend toward a higher one in the treatment group
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Ethical statements
This study was approved by the Ethics Committee of San Carlos Clinic Hospital (Madrid Complutense University, Madrid, Spain) (registry number: 10/335-E), and was conducted in accordance to the ethical
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standards laid down in the 1964 Declaration of Helsinki and its later amendments.
A written and verbal explanation was given of the study objectives, the possible side effects, and of the
informed consent document.
Suport
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importance of complying with normal dental hygiene. All participants in the study signed the corresponding
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Laboratorios Kin (Barcelona –Spain-) provided treatment and placebo toothpastes.
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Figure captions
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Fig. 1. Flowchart of the trial.
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fig 1.jpg
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Table 1. Mean and standard deviation (SD) for the ∆E value of all bleached teeth for both groups at 3, 6, 9 and 12 weeks follow-up.
3 weeks p =0.061
mean 3.13 3.89
SD 1.36 1.07
Control Treatment
6 weeks p =0.448
3.25 4.02
1.62 1.89
Control Treatment
9 weeks p =0.114
3.61 4.19
1.35 1.77
Control Treatment
12 weeks p =0.064
3.83 4.23
1.13 1.57
Ac ce pt e
Control Treatment
Table 2. Mean and SD L*a*b* EW values of all bleached teeth for both groups at baseline and 12 weeks follow up.
L* Baseline
Control
mean 79.76
SD 3.63 12
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3.61 3.93 3.41
Control Treatment Control Treatment
-0.88 -0.67 -0.84 -0.77
0.09 0.08 0.09 0.08
Control Treatment Control Treatment
20.70 20.65 20.60 20.19
3.57 3.67 4.01 2.74
Control Treatment Control Treatment
29.39 29.15 29.13 28.68.
3.73 3.80 3.78 3.46
ip t
79.86 79.25 80.14
Ac ce pt e
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a* Baseline p=0.452 12 weeks p=0.779 b* Baseline p=0.835 12 weeks p=0.133 EW Baseline p=0.738 12 weeks p=0.723
Treatment Control Treatment
cr
12 weeks p=0.673
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