Clinical Study on the Effectiveness and Side Effects of Hexetidine And

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Clinical study on the effectiveness and side effects of hexetidine and chlorhexidine mouthrinses versus a negative control Claus-Peter Ernst, Priv Doz Dr Med Dent1/ Kerem Canbek, Dr Med Dent2/Annette Dillenburger, Dr Med Dent3/ Brita Willershausen, Prof Dr Med Dent4

Objectives: The aim of this clinical, controlled double-blind trial was to evaluate the effec- tiveness and side effects of two different mouthrinses. Method and materials: Ninety sub- jects with gingivitis (or slight periodontitis) were randomly allocated to three groups: group 1, Chlorhexamed (0.1% chlorhexidine); group 2, Hexoral (0.1% hexetidine); and group 3, a placebo-control compound. The subjects were instructed on how to use the mouthrinse. At baseline, as well as after 2 and 4 weeks, the Approximal Plaque Index (API), the Bleeding Index (BI), the Community Periodontal Index of Treatment Needs, the Gingival Index (GI), and the Discoloration Index (DI), were measured. Statistical analysis was car- ried out with the Kruskal-Wallis test, Fisher´s exact test, and Wilcoxon test. Results: In group 1, the mean API improved significantly (P ≤ .001) after 4 weeks. The mean BI was reduced significantly, as was the GI. In group 2, the mean API and the mean BI both decreased significantly, and a statistically significant reduction of the GI was also seen. In group 3, significant improvements of the mean values of all parameters were documented after 4 weeks. When comparing group 3 with groups 1 and 2, the difference in the reduc- tion of the API was statistically significant (P < .002). No statistical difference could be shown when comparing groups 1 and 2. Regarding the improved results of the BI and the GI, no statistically significant difference was found in the effectiveness of all 3 compounds. All 3 groups showed some increase in the mean DI after 4 weeks. Comparing groups 1 and 2 directly, the difference in the increase in the discoloration of the teeth was statistical- ly significant (P = .0035). There was no statistical difference in the mean discoloration scores comparing groups 2 and 3. Conclusion: This double-blind clinical trial demonstrat- ed Hexoral to be a useful alternative to Chlorhexamed mouthrinse, as well as one causing less discoloration. (Quintessence Int 2005;36:641–652)

Key words: chlorhexidine, discoloration, gingivitis, hexetidine, mouthrinses, plaque

Plaque plays a decisive role in the etiology of 1Associate Professor, Department for Operative Dentistry, caries, gingivitis, and inflammatory periodon- Johannes Gutenberg University Mainz, Mainz, Germany. tal diseases. Therefore, an efficient removal of 2Assistant Professor, Department for Operative Dentistry, Johannes Gutenberg University Mainz; and private practice, this organized biofilm and the reduction of its Mainz, Germany. formation is a necessary and indispensable

3Department for Operative Dentistry, Johannes Gutenberg requirement to effectively prevent caries, gin- University Mainz; and private practice, Worms, Germany. givitis, and inflammatory periodontal diseases. 4Professor and Head, Department for Operative Dentistry, In addition to the conventional practice of Johannes Gutenberg University Mainz, Mainz, Germany. mechanically cleaning teeth with toothbrush- Reprint requests: Dr Claus-Peter Ernst, Department for es, dental floss, toothpicks, and interdental Operative Dentistry, Johannes Gutenberg University Mainz, Augustusplatz 2, D55131 Mainz, Germany. E-mail: ernst@ brushes, the chemical reduction of plaque uni-mainz.de with mouthrinses can play a decisive role.

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Brushing teeth twice a day is commonly Compared with chlorhexidin mouthrinses, accepted as a minimum level of oral hygiene. quaternary ammonium compounds offer less Therefore, proper instruction in the appropri- reduction of plaque and gingivitis, although ate oral hygiene techniques, which include they have a higher adsorption and a longer cleaning all the surfaces of the teeth, is of substantivity.12,13 Side effects from these cate- prime importance for dental care. gory 2 rinses include discolorations, burning Additionally, as a prophylaxis against caries, tongue, and increased odontolithiasis.14 gingivitis, and other periodontal diseases, Hexetidin belongs to the group of pyrimi- chemical adjuvants for plaque control, which dine derivatives, which affect bactericide on are included as chemical amendments in gram–positive bacteria. After discovering the toothpaste and mouthrinses, are often recom- specific antibacterial and fungicidal effect of mended.1 Today’s requirements for effective hexetidin (hexahydropyrimidine), many clinical mouthrinses include an efficient antibacterial studies verified the sensitivity of bacteria impact, containment of bacterial proliferation, against hexetidin.15–17 Hexetidin is a competi- specificity opposite to oral bacteria,2 few side tive inhibitor of thyamine and has long been effects, a sufficiently long retention time (sub- used for disinfection in the oral cavity and stantivity), and stability during storage.3 the pharynx because of its pharmacological, Today’s common mouthrinses can be subdi- toxicological, and antimicrobial character.15 vided into 3 nonchronologic categories.4 Because of its affinity to proteins of the oral mucosa and plaque, hexetidin may reduce as • Category 1 solutions: These are sub- much as 98% of saliva germs directly after stances with high specificity and efficien- rinsing. Oral retention is low, however, as the cy, but with low substantivity, such as phe- bacterial values in the oral cavity return to their nol, quaternary ammonium compound, initial values after 70 to 90 minutes.3,18 pyrimidine derivative, plant essence, and Hexetidine is more efficient when combined fluoride (excluding aminfluoride). with zinc. Hexetidine/zinc compounds inhibit • Category 2 solutions: The antimicrobial the formation of plaque and gingivitis almost mouthrinses of category 2 have high speci- totally, which is similar to chlorhexidine.19 ficity and efficiency as well as high sub- The largest plaque-inhibiting effect of stantivity. They consist of the group of bis- fluoride-containing mouthrinses is shown by biguanides (chlorhexidin, alexidin). amine-fluorid combined with tin-difluorid. • Category 3 solutions: These mouthrinses Although it has been proven that combined are surface-active substances which cause compounds of this kind have a noticeable a reduction in the adhesion of oral microflo- antibacterial effect, clinical studies reveal a ra on enamel surfaces.5,6 These solutions lower inhibition of plaque as compared to have no specific antibacterial effect.7,8 chlorhexidine.9,20 Chlorhexidine compounds have been Phenols affect the proliferation of used for years in different medical specific gram–negative bacteria by neutralizing the fields because of their diverse and distinctive bacteria and inactivating their endotoxins. It bactericide and bacteriostatic effects,2,21 as has been shown that small concentrations well as their water-soluble quality.22 provide an anti-inflammatory effect, but Chlorhexidine obtains its bactericide effect whether phenols can provide critical interfer- through precipitation, coagulation, and extru- ence against the microorganisms of sion of cell membranes subjected to its supragingival plaque has yet to be proven.9 concentration.2,23–26 It is efficient against The substantivity of phenols must be regard- gram-positive and gram-negative bacteria, as ed as low for now. well as against fungi and yeasts.27 The substantivity of quaternary ammonium Chlorhexidine shows a high affinity to oral compounds also must be regarded as low. A mucosa, dental surface, and saliva glucopro- 25% to 35% reduction of plaque was teins.28 Its prolonged performance, which is obtained during short-term studies.10,11 also responsible for its high antibacterial

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effect in vivo,29 is obtained by unleashing Mouthrinse A contained Chlorhexamed active compounds after 8 to 12 hours.30 (GlaxoSmithKline), mouthrinse B contained The aim of this double-blinded clinical Hexoral (Warner-Lambert), and mouthrinse C study was to compare the effectiveness of contained the control (placebo) compound. chlorhexidine and hexetidine in regard to Mouthrinse A contains 0.1% chlorhexidine reduction in plaque and gingivitis; and to digluconate as an active agent. Ethanol, glyc- determine if, and to what extent, both com- erol, macrogol-glycerolhydroxystearate, fla- pounds lead to discoloration and further side voring agent, and pigment E 124 are added effects, such as changes in the sense of taste as adjuvants. Hexetidine (0.1%) is the active and changes of the oral mucosa and its agent in mouthrinse B. Anise oil, cineol, citric sensitivity. Due to the many known side acid, ethanol (96%), menthol, methylsalicy- effects, such as hypersensitivity of the late, pink oil, peppermint oil, polysorbate 80, mucosa, discoloration of teeth, hairy tongue, saccharine-sodium, purified water, and pig- and interference in the sense of taste, ment E 123 were added as adjuvants. chlorhexidine should be applied for no Mouthrinse C contains propyleneglycol, glyc- longer than 4 weeks. Hexetidine has no tem- erol, gentian-tincture, pigment E 124, and poral restrictions. Therefore, a clinical appli- purified water. Group 1 rinsed with cation of a hexetidine compound, which mouthrinse A, group 2 with mouthrinse B, seems to have few side effects in terms of dis- and group 3 with mouthrinse C. coloration, and a comparatively active spec- The subjects were given detailed instruc- trum such as chlorhexidine, would be an tions on oral hygiene. Each subject received interesting alternative and may be advanta- a new toothbrush (Oral B, P 35, Gillette/Oral geous for many dental situations. B) and several trial packages of a standard- ized toothpaste (Elmex, Gaba). The subjects were asked to brush their teeth with the new toothbrush and toothpaste after breakfast METHOD AND MATERIALS and dinner each day. Subjects were asked to rinse with 15 mL of the undiluted mouthrinse A total of 101 subjects, 74 soldiers stationed in for 30 seconds after each brushing. Mainz, Germany, and 27 students from the The study lasted for 4 weeks. Each sub- dental clinic of Johannes Gutenberg Univer- ject was examined 3 times during the 4 sity Mainz, Germany, were divided randomly weeks. The oral examination measured the into three groups. Each volunteer had gingivi- modified Approximal Plaque Index (API);31 tis or slight periodontitis. General exclusion the Bleeding Index (BI);32 the Decayed, criteria were systemic diseases and long-term Missing, and Filled Teeth Index (DMF-T);33 medications. Eleven subjects were dropped the Community Periodontal Index of Treat- from the study due to noncompliance. The ment Needs (CPITN);34 the Gingival Index remaining 90 stayed in the program until the (GI);35 and the Discoloration Index (DI). The end. The mean age of the subjects was 28.4 DI was scored as follows: 0, no discoloration; 1 (± 8.5) in group 1, 32.2 (± 12.2) in group 2, 1, discoloration up to ⁄3 of tooth surface; 2, 2 and 31.3 years (± 9.5) in group 3. discoloration up to ⁄3 of the tooth surface; 3, All mouthrinses were coded and placed discoloration of entire tooth surface. After into identical bottles. The bottles were labeled A, each examination the subjects were ques- B, or C by the pharmacy at the University Clinic tioned about their coffee, tea, and cigarette Mainz, Mainz, Germany. The solutions were consumption and usage. handed out randomly to each subject. Each The plaque and the soft covering on the solution contained the same application and tooth surface were dyed with a 2-colored dosage instructions. The bottles were not decod- plaque-indicator (Oral B) to determine the ed until after all the follow-up examinations and API. Each subject’s teeth were professionally final statistical analyses had been completed, cleaned afterwards. Insistent stains and dis- ensuring a proper double-blind study protocol. colorations were removed with an Airflow

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instrument (Kavo), as well as with conven- Group 3 was given the control compound, tional polishing brushes and polishing paste or mouthrinse C. The group consisted of 28 (Zircate Prophy, Dentsply/DeTrey). subjects, whose ages ranged from 22 to 54 A second examination was performed 2 years (mean age 31.3 ± 9.5 years). Eighteen weeks after the first exam. The GI and DI of the 28 drank coffee, and 15 drank tea. were measured, and subjects were asked Eight were smokers. The mean DMF-T value about changes to their sense of taste, sensi- of group 3 was 14.2 ± 5.9. Due to the small tivities of the oral mucosa, and the taste of the number of subjects, no further group combi- mouthrinse. Any changes in the oral mucosa nations were examined, ie, smokers/coffee were examined and, if applicable, changes drinkers or coffee/tea drinkers. were documented and photographed. The mean DMF-T value for all groups was The final examination was conducted after 14.7 ± 6.1. 4 weeks. The API, BI, CPITN, GI, and DI were measured. The subjects were questioned Community Periodontal Index of again about sensitivities of the oral mucosa Treatment Needs and changes in the sense of taste. Each sub- After 4 weeks, CPITN value showed a dis- ject’s teeth were professionally cleaned to tinct, although not statistically significant remove any possible new discolorations. The improvement (P = .9258) from the baseline subjects were asked about their objective CPITN values in all 3 groups. The mean perception about the mouthrinse. CPITN value of group 1 went from 2.8 ± 0.7 All exams were done by clinicians at the to 2.6 ± 0.9. The mean CPITN value in group Department of Operative Dentistry, Johannes 2 declined from 2.9 ± 0.7 to 2.4 ± 1.1. A slight Gutenberg University. shift was seen in group 3, moving from 2.8 ± The data were documented using Excel 0.7 to 2.6 ± 1.0. data shields, and the final statistical evalua- tion was carried out using the SAS program Approximal Plaque Index (SAS). The Kruskal-Wallis test, the Fisher’s An improvement in the mean API values was exact test, and the Wilcoxon test (paired and seen in all 3 groups (Fig 1). The results were unpaired) were used at the 5% level of statis- compared after the 4-week study to point out tical significance for the statistical evaluation. differences in the efficiency of the 3 mouthrinses. In this consideration, a statisti- cally significant difference (P = .0002) was given. The mean API values in group 1 were RESULTS reduced 47.5%, from 73.4 ± 18.6 to 38.5 ± 23.2. In group 2, a mean reduction of 40.0%, Out of the initial 101 subjects accepted for from 69.0 ± 21.3 to 41.4 ± 21.0, was found. the study, 90 remained until the end. Even in group 3, the control group, a reduc- Group 1, who received mouthrinse A, tion of the API of 20.2%, from 67.2 ± 25.1 to consisted of 33 subjects, whose ages 53.6 ± 20.4, was found (Fig 1). ranged from 18 to 50 years (mean age 28.4 No statistically significant differences ± 8.5 years). Twenty-four of the 33 subjects were found when comparing the change drank coffee regularly, and 18 drank tea. between the baseline and final API values for Seventeen of the 33 smoked cigarettes. The mouthrinse A with that of mouthrinse B (P = mean DMF-T value of group 1 was 16.3 ± 6.7. .3370). Compared to mouthrinse C, signifi- Group 2, which received mouthrinse B, cant differences in the efficiency of the irrig- consisted of 29 subjects, whose ages ants could be obtained with mouthrinse A ranged from 22 to 58 years (mean age 32.2 (change between baseline and final API val- ± 12.2 years). Twenty-four of the 29 drank ues: P = .0001), as well as with mouthrinse B coffee, and 12 drank tea. Twelve were smok- (change between baseline and final API val- ers. The mean DMF-T value of group 2 was ues: P = .0022). 13.8 ± 5.3.

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100 1.2 90 1.0 80 73.4 70 69.0 0.8 67.2 0.66 60 0.66 53.6 50 0.6 0.65 0.48 API (%) 41.4

40 Bleeding Index 38.5 0.4 0.40 30 0.38 Chlorhexamed 20 Chlorhexamed 0.2 Hexoral 10 Hexoral Placebo Placebo 0 0 Baseline 4 weeks Baseline 4 weeks

Fig 1 Mean scores and standard deviation of the Fig 2 Mean scores and standard deviation of the Bleeding Index (BI) for Approximal Plaque Index (API) for the mouthrinses at baseline the mouthrinses at baseline and after completion of the study. and after the completion of the study.

Bleeding Index obtained during the intermediate check-up, After the 4-week trial, a significant improve- as well as during the final examination ment in the results of the BI of all 3 (P < .001; Fig 3). mouthrinses was obtained (Fig 2). The mean The mean GI value of mouthrinse A was BI value of mouthrinse A decreased from reduced 41.8% from 1.21 ± 0.68 at baseline 0.66 ± 0.31 at baseline to a final BI of 0.38 ± to 0.71 ± 0.54 at the intermediate check-up. 0.24 with a significant difference (P = .0001) The overall reduction to the final value of at a mean of 0.28 ± 0.21. 0.45 ± 0.45 was 62.3%. The mean BI of mouthrinse B decreased The GI of mouthrinse B decreased from a from 0.65 ± 0.34 to a BI of 0.40 ± 0.34 with a mean of 1.11 ± 0.88 to 0.60 ± 0.48 (–46.4%) significant difference (P = .0001) of 0.28 ± at the intermediate check-up to a final value 0.30. of 0.47 ± 0.49 (–57.1% overall). Even mouthrinse C showed a reduction in Mouthrinse C also showed a GI improve- bleeding, and the mean BI value went from ment. The GI was reduced 29.4% from a 0.66 ± 0.33 at the beginning to 0.48 ± 0.34 baseline level 1.09 ± 0.71 to 0.77 ± 0.56% at at the end, with a significant difference the intermediate check-up and a final value of (P = .0001) of 0.19 ± 0. 25. 0.56 ± 0.49 (–48.6% overall). Comparing all 3 mouthrinses directly, no No statistically significant difference could relevant difference could be obtained in the be found when comparing all 3 mouthrinses efficiency in relation to an improvement in the directly (P value difference appointment 0 to BI. The P value of the difference in BI (from 2 in comparison: P = .2126; P value differ- baseline to end) was P = .2997 when com- ence 0 to 1: P = .4064). A direct comparison paring all 3 solutions directly. This was not a between 2 mouthrinses such as A and B (dif- significant difference. ference-GI 0–2: P = .4503), A and C (differ- According to the comparison between 2 ence-GI 0–2: P = .0811), or B and C (differ- mouthrinses, eg, A and B (P = .6979), A and ence-GI 0–2: P = .3341) showed no statisti- C (P = .2240), or B and C (P = .1577), there cally significant differences in the efficiency were no statistically relevant differences. of the mouthrinses.

Gingival Index Discoloration Index A significant improvement of the baseline val- The DI was taken only during the intermedi- ues of the GI (GI 0) of all 3 mouthrinses was ate and final check-ups, not at the initial one,

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2.5 1.2 Chlorhexamed Chlorhexamed Hexoral 1.0 Hexoral 2.0 Placebo Placebo 0.8 1.5 0.69 1.21 0.6 1.11 1.0 Gingival Index Gingival 1.09 0.4 0.43 0.77 Index Discoloration 0.71 0.34 0.25 0.5 0.60 0.56 0.47 0.2 0.22 0.45 0.11 0 0 0 Baseline (GI 0) 2 weeks (GI 1) 4 weeks (GI 2) Baseline (DI 0) 2 weeks (DI 1) 4 weeks (DI 2)

Fig 3 Mean scores and standard deviation of the Gingival Index (GI) for the Fig 4 Mean scores and standard deviation of the mouthrinses at baseline (GI 0), after 2 weeks (GI 1), and after completion of Discoloration Index (DI) for the mouth rinses at baseline (DI 0), the study (GI 2). after 2 weeks (DI 1), and after completion of the study (DI 2).

because all exogenic stains had been (DI 1, P = .1464) or after 4 weeks (DI 2, P = removed at the baseline examination and the .1262) when comparing mouthrinses B and C. DI was, therefore, at zero. The subjects were asked about changes During the intermediate check-up (DI 1), in their sense of taste and sensitivities of the mouthrinse A showed a mean of 0.34 ± 0.33 oral mucosa; they were also asked to rate the and a DI 2 (final check-up) after a total of 4 taste of their mouthrinse at the intermediate weeks of 0.69 ± 0.39; while the mean DI of and final check-ups. A total of 28 of 90 sub- mouthrinse B at DI 1 was 0.22 ± 0.33 and jects reported obvious changes in their 0.43 ± 0.47 at DI 2. sense of taste after using the mouthrinse. Even mouthrinse C showed an increasing The number of subjects using mouthrinse B mean DI from 0.11 ± 0.1 at the intermediate reported the most incidences of a change in check-up to 0.25 ± 0.29 at the end of the 4- their sense of taste. A total of 18 of 29 sub- week irrigation period. jects (62.1%) complained about changes in When comparing all 3 mouthrinses, a sta- their sense of taste. Only 8 of 33 subjects tistically significant difference was seen, (24.2%) using mouthrinse A reported a according to discoloration, after using the change in the sense of taste. In the group solutions at the intermediate check-up (P = using mouthrinse C, 2 out of 28 subjects .0056), as well as at the final examination (P (7.1%) complained about obvious changes in = .0001; Fig 4). Therefore, a direct compari- their sense of taste. son of the results of 2 mouthrinses was con- All 90 subjects were asked about sensitiv- ducted. A direct comparison between ities of the oral mucosa after using their mouthrinses A and B showed no statistical assigned mouthrinse. A relatively high num- significance after 14 days (DI 1, P = .0757). ber of subjects using mouthrinse B com- After 4 weeks, the discoloration of the sub- plained about oral mucosa sensitivities. Two jects’ teeth using mouthrinse A was signifi- subjects out of this group showed such cantly higher than that of the subjects using severe changes in terms of intensive red, mouthrinse B (P = .0035). inflamed areas at the intermediate check-up This difference was more obvious when that mouthrinse use was discontinued imme- comparing mouthrinses A and C—the statisti- diately. The changes of the oral mucosa were cally significant P value was already P = photographically documented. .0015 at the intermediate check-up and P = In group 1 (using mouthrinse A), 5 of 33 .0001 at the final examination. No statistically subjects (15%) showed sensitivities of the oral significant difference was seen after 14 days mucosa. None showed severe enough changes to warrant discontinuing use of the

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mouthrinse. There were no changes of the oral phylaxis and the battle against gingivitis, peri- mucosa in the 28 subjects using mouthrinse C. odontal disease, and caries. An increasing A total of 24% of the subjects in group 1 level of awareness about oral microbiology suffered from changes in their sense of taste. and plaque has led to the development of Seventeen out of the 33 subjects reporting specific strategies to use the antimicrobial these changes (52%) were smokers, 16 effect of chemical substances. (48%) were non-smokers. Seven non-smok- The efficiency of mouthrinses in the oral ers (43%) stated that they had obvious cavity depends on many different psycholog- changes of their sense of taste, while only 1 ical and physical factors. The different areas smoker (6%) stated the same. The P value of of the oral cavity are exposed differently to a this statistical test of the correlation of smok- mouthrinse depending on the location of the ers and changes in the sense of taste was secretory ducts of the salivary glands and the P = .017, so that non-smokers reported signif- salivary secretion. Accordingly, it is vital that icantly more changes while using mouthrinse the mouthrinse agent has an appropriate A than did smokers. Furthermore, 5 non- substantivity,3 as well as an initial bactericidal smokers suffered from slight sensitivity of the effect, so that through a higher adhesion on oral mucosa after rinsing, a phenomenon the tooth surface and the oral mucosa, the which was not reported by any of the sub- effectiveness is prolonged. jects who smoked. This statistically signifi- The efficiency and possible side effects of cant P value was P = .018. mouthrinses A and B, as well as that of A total of 62% of 29 subjects suffered mouthrinse C, was investigated in this clinical from changes in their sense of taste while double-blinded trial. Both hexetidine and using mouthrinse B. Group 2 (using chlorhexidine have a proven plaque- and gin- mouthrinse B) consisted of 63% non-smok- givitis-reducing effect. Their efficiency was sig- ers and 37% smokers. Of the non-smokers, nificantly higher than that of a negative control 85% complained of changes in their sense of compound and an amine-fluoride solution.19 taste during the study, whereas only 33% of Chlorhexidine is one of the most investi- the smokers complained. This was statisti- gated antiseptic agents in dentistry today.36 cally significant (P = .006). After using The studies vary in the duration of timeframe, mouthrinse B, non-smokers reported signifi- the number of subjects, and the indices cantly more changes in their sense of taste measured. These differences make a direct than smokers reported. No statistically signifi- comparison between these studies difficult. cant correlation between the smoking behav- In 1985, for example Gängler and Staab37 ior of the subjects, and interferences in the investigated the effectiveness of chlorhexi- sense of taste and response changes of the dine digluconate on the formation of plaque oral mucosa could be obtained in group 3. over 2 years, but with only 28 subjects. At the final examination, all subjects were Frentzen et al38 tested the efficiency of a 40% asked for their subjective evaluation of the chlorhexidine-enamel varnish as an adjuvant taste of the mouthrinse they used. The in caries prevention. They determined after a responses from group 3 (those using the single application, that the quantity of cul- placebo) attracted special attention in this sur- tivable Streptococcus mutans colonies was vey. A total of 20 of 28 subjects in group 3 reduced significantly in 6 weeks, with rated the taste of mouthrinse C as bad. Most patients showing an increased plaque accu- of the subjects in groups 1 and 2 rated the mulation (API ≥ 30%). The evaluation taste of their mouthrinses as medium (Fig 5). showed that subjects with a high plaque accumulation had an appropriate reduction of the API. A microbiologic test on S mutans by means of a Dentocult SM test showed DISCUSSION comparable results. Given that a direct corre- lation between a verifiable number of S In today’s Western population, mouthrinses mutans and the probability of developing are widely accepted adjuvant agents for pro- caries exists, the application of a chlorhexi-

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Mouthrinse A = Chlorhexamed Mouthrinse B = Hexoral Mouthrinse C = Placebo

15.2 14.3 24.2 24.1 24.1

14.3

60.6 51.7 71.4

Good Medium Poor Good Medium Poor Good Medium Poor Fig 5 Evaluation of the taste of mouthrinses A, B, and C by the subjects.The choice of ratings was “good,”“medium,”or “poor.”

dine enamel varnish can be termed as an Changes in the sense of taste not only effective means in preventing caries.38 interfere with the gustatory sense, but can Chlorhexidine inhibits the vitality of the last several hours (lasting hypo- and dysgeu- plaque flora39,40 and, therefore, also inhibits sia).45 A study on changes in the sense of the formation of new plaque40 and reduces taste after using a chlorhexidine mouthrinse the plaque’s metabolism. showed that the taste perceptions of bitter Because of its affinity to the oral mucosa, and salty were interfered with most.48 chlorhexidine reduces the amount of bacte- Rushton47 reported changes of the sense ria in the oral cavity up to 90% after only a few of taste in one-third of his patients, which all minutes, and remains highly efficient for sev- turned out to be reversible after discontinu- eral hours.42 ing use of the mouthrinse. In comparison with an amine-chloride All 22 subjects in a study done by mouthrinse, Gräber42 documented a signifi- Gängler and Staab37 suffered from changes cant reduction of the API and GI after using a in their sense of taste for 2 years. Mostly the mouthrinse containing chlorhexidine diglu- sense of sweet was affected, followed by the conate for one week. Richter et al43 proved perception of salty and sour. this plaque- and gingivitis-reducing effect In this study, it was notable that a pre- even at a 0.05% concentrated chlorhexidine dominant number of non-smokers experi- solution. Sixty-four subjects with an experi- enced changes in their sense of taste com- mental gingivitis were studied for 3 weeks. pared with smokers. This is likely due to the The subjects used 15 mL of a 0.05% fact that the daily consumption of tobacco chlorhexidine mouthrinse or a negative-con- and nicotine can dull the sensitivity of the trol compound for 30 seconds twice a day. It gustatory receptors. Furthermore, patients was also documented that the application of who consume cigarettes, tea, and coffee a 0.1% chlorhexidine gel led to a significant tend to reinforce discolorations of the tooth reduction of papillary and marginal inflam- surface and of restorations. mation after only 1 week of use.43 A study done by Albandar et al49 involved The side effects of chlorhexidine are a pop- 10% of all Norwegian dentists, sharing their ular subject of study. Tooth discoloration, espe- experience with chlorhexidine over the past cially in composite restorations,36,44–46 changes 20 years. Most of them reported prescribing in the sense of taste,37,47 and sensitivities of the chlorhexidine after surgical periodontal inter- oral mucosa are often documented.37 ventions (85%), for the treatment of acute gin-

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givitis (74%), or after common surgical inter- product.54 Schaller and Hahn55 used a spray ventions such as extractions (57%). Seventy- containing a mixture of hexetidine during seven percent of the questioned clinicians phases of complicated oral hygiene. Their reported discolorations of the tooth surface, study showed that this combination inhibited restorations, and the tongue; 12% reported the formation of new plaque, and reduced patient discontent regarding the bitter taste of the onset of gingivitis. the mouthrinse; and 6% reported cases of dry The manufacturer of the hexetidine mouth and sensitivities of the oral mucosa. mouthrinse Hexoral (Warner-Lambert) speci- Only 14% of the dentists who participated in fies side effects of hypersensitive reactions the study reported they never prescribe and changes in the sense of taste after appli- chlorhexidine.49 cation. The erosive effect of hexetidine com- Hexetidine belongs to the group of pyrim- pounds on tooth enamel have been docu- idine derivatives and is allocated to category mented.56 Other studies have shown that 1 mouthrinses.50,51 Many studies revealed nearly every antiseptic mouthrinse can cause hexetidine’s efficiency against gram-positive tooth surface and composite restoration dis- bacteria.16,17 Because of its bactericidal, as coloration.29 Sensitivities of the oral mucosa, well as its fungicidal qualities, hexetidine has including redness, slight epithelium desqua- been used for disinfection and purification of mations, and burning, were documented the oral cavity for many years. It has great after rinsing with Chlorhexamed (5 subjects) value for this application, as hexetidine com- and Hexoral (10 subjects). pounds have a high affinity for proteins of the Several such sensitivities of the mucosa oral mucosa, as well as for plaque on tooth have been described in the literature. surfaces.The intraoral bacteria reduction Aphthoid lesions and plain epithelium must be seen as rather short-lived because desquamations have been described as of the low substantivity of hexetidine com- well.45 Very red areas have exposed the pounds.52 Several studies revealed that there superficial stratum. These changes of the was, in fact, a reduction of salivary bacteria of mucosa coincided with strong burning pain, about 98% of the initial value immediately which were reinforced with fruit acids. The after rinsing with hexetidine, but the bacteria areas involved healed after discontinuing values rose back to the initial levels after 70 mouthrinse use. to 90 minutes because of the low intraoral In our study, all subjects were informed retention.18 A further study on the antibacteri- about the reasons for inflammatory periodon- al effect of hexetidine showed no decrease in tal diseases, particular spots which might cre- the concentration of the agent in saliva sub- ate difficulties, and problems during individ- jected to time and dose, but it was also proven ual daily oral hygiene procedures, as well as that no antibacterial effect of the salivary sam- appropriate cleaning methods of teeth and ples could be obtained after 30 minutes.17 approximal areas. These facts led to a better A double-blinded study with 38 patients understanding of oral hygiene and to higher done over 28 days showed significant subject motivation, which was increased after plaque reduction, as well as an obvious the intermediate check-up. This seems to be improvement in wound healing after surgical the reason for the improvement of the API periodontal interventions when using a 0.2% and BI in group 3, which used the agent-free hexetidine spray.53 No differences were negative-control compound. shown in comparison to a negative-control The API improved significantly (P ≤ .05) in compound on the efficiency of a 0.1% hexe- all 3 groups, whereas group 1 (using tidine mouthrinse on the microflora of aph- mouthrinse A) showed the most obvious thoid ulcerations. The treatment of patients improvement (about 35%), followed by group with recurring small aphthoid lesions with a 2 (using mouthrinse B) with 29% and, surpris- daily application of a 0.1% hexetidine ingly, 14% for group 3. The results for BI were mouthrinse, in addition to conventional oral similar: The BI of group 1 decreased 42.4%, hygiene methods, showed no improvement and group 2 improved by 38.5%. Group 3 compared to those using a negative-control showed an improvement of 27.5%.

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According to the GI, nearly identical CONCLUSIONS improvements could be obtained with mouthrinses A and B. The GI was only visual- ly surveyed and, therefore, the results may be 1. This double-blinded clinical trial document- imprecise. The differences between groups ed that, to a certain extent, mouthrinse 1 and 2 were so low that they were not of any containing 0.1% hexetidine could be a statistical importance, but the improvement viable alternative to a mouthrinse contain- of the values after 2 weeks was notable. ing 0.1% chlorhexidine. For DI measurements, group 1 showed the 2. A mouthrinse containing 0.1% hexetidine highest increase in values. The results dou- caused significantly less discoloration to bled after the intermediate check-up to the tooth surfaces and restorations over a final examination, whereas the discolorations period of 4 weeks (P = .0035). in group 1 were statistically and significantly 3. The 0.1% hexetidine mouthrinse can be higher than those of group 2. Subjects of applied longer than the 0.1% chlorhexi- group 3 also showed slight discolorations. dine without risk of side effects. Individual variations of discolorations were 4. This study showed that, above all, appro- noticeable during this study, depending on priate oral hygiene, as well as an explana- the oral hygiene of the subjects. In a study on tion to and acceptable motivation of 57 undesirable side effects, Solheim et al deter- patients by practitioners, play an impor- mined that applying a 0.2% chlorhexidine tant role. This can be seen from the results mouthrinse led to individual discoloration vari- of group 3, who rinsed with an agent-free ations. Furthermore, they described a correla- negative-control compound, and still tion between the plaque-reducing effect of improved their results. chlorhexidine and the tendency to discolor tooth surfaces, caused by cationic retention of chlorhexidine on oral mucosa and teeth.57 In a 6-month study using a 0.12% chlorhexidine-containing toothpaste, Sanz et REFERENCES al58 documented an obvious increase of dis- coloration on tooth surfaces and restorations. 1. Plagmann HC. Lehrbuch der Parodontologie. In that study, the increase in intensity of dis- Munich: Hanser-Verlag, 1998:278–281, 330. coloration, as well as the circumference on 2. Lange DE. Über den Einsatz von Chlorhexi- tooth surfaces, was statistically significant.58 dindigluconat (CHX) als antimikrobiell wirkendes Medikament in der Stomatologie. Dental Forum The relatively small number of subjects 1995;2:9–15. (90) in our study must be addressed. It might 3. Baumann AM. Grundlagen der Zahnerhaltungs- be possible that in a study encompassing a kunde, 1995:40–46. [Self-published] higher number of subjects, differences docu- 4. Netuschil L. Zukünftige Plaque- und Chemother- mented as not significant may turn out to be apie-Konzepte. Oralprophylaxe 1991;13:47. significant, taking into account that the level 5. Simonsson T, Hvid EB, Rundegren J, Edwardsson S. of the standard deviation will stay with more Effect of delmopinol on in vitro dental plaque for- subjects, but the random error decreases at mation, bacterial acid production and the number of microorganisms in saliva. Oral Microbiol the same time. Immunol 1991;6:305–309. Most studies on the efficiency of chlorhex- 6. Freitas LB,Rundegren J,Arnebrant T.The binding of idine and hexetidine mouthrinses have been delmopinol and chlorhexidine to Streptococcus carried out with less than 100 subjects, and mutans and Actinobacillus actinomycetemcomitans a study with a substantially higher amount of strains with varying degrees of surface hydrpho- subjects, eg, about 1,000, could be of great bicity. Oral Microbiol Immunol 1993;8:355–360. scientific and medical interest. 7. Rundegren J, Hvid EB, Johansson M, Astrom M. Effect of 4 days of mouth rinsing with delmopinol or chlorhexidine on the vitality of plaque bacteria. J Clin Periodontol 1992;19:322–325.

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