|Year : 2016 | Volume
| Issue : 2 | Page : 54-59
Assessing the effectiveness of systemic tinidazole as an adjunct to nonsurgical periodontal therapy in the treatment of chronic periodontitis in smokers: A randomized double-masked, placebo-controlled clinical trial
Farin Kiany1, Armaghan Tarjan2, Fatemeh Moloudi3
1 Department of Periodontics, Dental School, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Dental, Dental School, International Branch, Shiraz University of Medical Sciences, Shiraz, Iran
3 Department of Periodontics, Dental School, International Branch of Shiraz University of Medical Sciences, Shiraz, Iran
|Date of Web Publication||16-Jun-2016|
Department of Dental, Dental School, International Branch, Shiraz University of Medical Sciences, Shiraz
Source of Support: None, Conflict of Interest: None
Background: The aim of this clinical trial was to evaluate the effectiveness of systemic tinidazole as an adjunct to nonsurgical periodontal therapy in the treatment of chronic periodontitis in smokers. Materials and Methods: Sixty smoker participants with history of moderate to severe generalized chronic periodontitis were selected. Gingival index (GI) Leo and Silness, plaque index (PI) O'Leary, bleeding index (BI) Lenox, pocket depth (PD), recession, and clinical attachment level (CAL) were measured at the baseline and 6 weeks after initial periodontal treatment. Thirty participants were randomly assigned to full-mouth scaling and root planning (SRP) + placebo (control group) and 30 participants were assigned to full-mouth SRP + tinidazole (test group). Results: Both test and control groups showed significant improvement in clinical parameters. Comparison of reduction in PI, GI, BI, PD, and CAL, between two groups, was statistically significant 6 weeks after baseline visit (P < 0.001). The improvements in clinical periodontal parameters were significantly more in test group. Conclusion: Smokers with chronic periodontitis benefited from adjunctive therapy, consisted of systemic tinidazole and SRP.
Keywords: Chronic periodontitis, nonsurgical periodontal debridement, smoking, tinidazole
|How to cite this article:|
Kiany F, Tarjan A, Moloudi F. Assessing the effectiveness of systemic tinidazole as an adjunct to nonsurgical periodontal therapy in the treatment of chronic periodontitis in smokers: A randomized double-masked, placebo-controlled clinical trial. J Dent Res Rev 2016;3:54-9
|How to cite this URL:|
Kiany F, Tarjan A, Moloudi F. Assessing the effectiveness of systemic tinidazole as an adjunct to nonsurgical periodontal therapy in the treatment of chronic periodontitis in smokers: A randomized double-masked, placebo-controlled clinical trial. J Dent Res Rev [serial online] 2016 [cited 2022 Jun 27];3:54-9. Available from: https://www.jdrr.org/text.asp?2016/3/2/54/184211
| Introduction|| |
Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth that result in the progressive damage of the periodontal ligament and alveolar bone with pocket formation, recession, or both. Periodontitis is the result of multifarious agents that include specific bacterial species that form biofilms on dental surfaces. Also both environmental and genetic factors can be as result of periodontitis. Along with the environmental factors, smoking plays a noteworthy role in the pathogenesis of chronic periodontitis. There are a number of studies that report positive associations between dose and years of consuming tobacco products and the severity of periodontal disease. Overall, different researches have shown that the risk of developing periodontal disease in smokers is 2-fold to 5-fold in comparison to nonsmokers. It is also well known that smoking modifies the host response, including alterations in vascular function, neutrophil/monocyte activities, adhesion molecule expression, antibody production, release of cytokine, and inflammatory mediators. In addition, in smokers, the early signs of periodontal disease can be disguised because of the suppression of the inflammatory responses. This can certainly lead to diagnostic problems.,,,,,,, Moreover, smoking has been stated to diminish salivary osteoprotegerin concentrations in untreated and also treated chronic periodontitis patients. The definite mechanisms by which smoking contributes to the pathogenesis of periodontitis are not yet obviously understood. Besides being more susceptible to periodontal diseases, cigarette smokers respond less satisfactorily to periodontal treatment including scaling and root planning (SRP) and professional tooth cleaning. During the past two decades, based on the microbial etiology of inflammatory periodontal diseases, periodontists have considered antibiotic therapy as an adjunct to mechanical treatment. This antibiotic therapy is based on bacterial specificity., According to Loesche et al., most of the periodontal pathogens are anaerobic, which designates that most periodontal diseases can be identified and cured as anaerobic infections. As the preponderance of periodontopathogens is Gram-negative, a number of antibiotics purposely targeting Gram-negative anaerobic bacteria are in use for the treatment of periodontitis. Chronic periodontitis is not typically treated with antimicrobials although at the moment, there are reports that demonstrate improvements by joining SRP with antimicrobial agents. Silva et al. showed that metronidazole plus amoxicillin in adjunction to mechanical debridement presented short-term clinical and microbial benefits over SRP alone in the treatment of chronic periodontitis. Pradeep et al. showed that the adjunctive use of 0.5% azithromycin, in comparison to the placebo, resulted in noteworthy improvement in the clinical outcome for the treatment of chronic periodontitis among smokers. Dastoor et al. demonstrated that in heavy smokers, adjunctive systemic azithromycin in combination with pocket reduction surgery did not significantly enhance pocket depth (PD) reduction or clinical attachment level (CAL) gain. However, the authors declared that the clinical significance of adjunctive azithromycin may be valued by more rapid wound healing, less short-term gingival inflammation, and sustained reductions of periopathogenic bacteria. Despite the clinical profits obtained by this combined regimen of antibiotics, treatment with these drugs requires 7–14 days at a dosage frequency of 3–4 times/day. Consequently, the likelihood of noncompliance would be increased noticeably. In addition, a relatively wide range of side effects and emergence of resistant bacteria have been reported with the extensive consumption of combination of metronidazole and amoxicillin. Lately, a variety of imidazole derivatives such as satrinidazole, ornidazole, and tinidazole are widely used for the treatment of infections caused by periopathogens including Gram-negative aerobic and anaerobic bacteria. Tinidazole is a second generation member of 5-nitroimidazole. It was primarily introduced into clinical medicine in 1969 for antiparasitic treatment of trichomonas vaginalis infections. Tinidazole displays a half-life of 12–14 h (doubling that of metronidazole), hence permitting once daily usage. Therefore, it appears that the comfort and compliance of patients are increased. In daily doses up to 2 g, it has no toxicity. Tinidazole is almost totally absorbed after oral administration. 1 g single dose administration of tinidazole leads to saliva concentrations, which are measurable up to 7 days. The side effect profile of tinidazole is more favorable than metronidazole, which is more notable in gastrointestinal tolerability and less metallic taste. For over two decades, tinidazole has been broadly used in Europe as well as developing countries. Its administration has been associated with an established effectiveness and an acceptable tolerability.
Considering the abovementioned benefits of tinidazole and the need for discovering novel adjunctive methods for periodontal treatment of smokers, this study was conveyed. The aim of this study was to assess the effectiveness of systemic tinidazole as an adjunct to nonsurgical periodontal therapy in the treatment of chronic periodontitis in smokers.
| Materials and Methods|| |
This study was a single-center, double-masked, randomized, placebo-controlled clinical trial that evaluated the effect of adjunctive systemic tinidazole in the treatment of smokers with chronic periodontitis. Sixty smoker patients with moderate to severe chronic generalized periodontitis were recruited from the population referred to the Department of Periodontics, International branch of Shiraz University of Medical Sciences. A detailed medical, periodontal, dental, and smoking history was obtained from all the participants. Individuals who fulfilled the inclusion/exclusion criteria were invited to participate in the study. All eligible participants were meticulously up-to-dated about nature, potential risks, and profits of their participation in the study and written informed consent was obtained. They were also informed about the known side effects of tinidazole and possible gastrointestinal disturbances. This study protocol was approved by the Ethical Committee of the Shiraz University of Medical Sciences. This clinical trial has now been registered in IRCT and allocated a unique code: IRCT2015022521195N2.
Inclusion and exclusion criteria
Sixty systemically healthy individuals (52 males and 8 females, aged 25 to 57 years; mean age: 42.8 years) with untreated moderate to severe chronic generalized periodontitis were recruited into the study based on the current classification of the American Academy of Periodontology. The inclusion criteria were as follows: (1) ≥25 years of age; (2) presence of at least 15 teeth, excluding third molars; and (3) the participants were considered current smokers if they had smoked at least 100 cigarettes in their lifetime and reported that they were smoking at the time of the interview. The participants also stated no concern for quitting smoking. The exclusion criteria were as follows: (1) Subgingival SRP or surgical periodontal therapy in the previous year; (2) pregnancy; (3) nursing; (4) systemic diseases that could influence the initiation and progression of periodontal diseases (such as diabetes mellitus, osteoporosis); (5) using antibiotics in the preceding 6 months; (6) long-term administration of anti-inflammatory drugs; (7) continuous use of antimicrobial mouth-rinses; and (8) established or suspected intolerance or allergy to 5-nitroimidazole derivatives.
The clinical parameters that were recorded included the followings: Plaque index (PI) O'Learry, bleeding index (BI) Lenox, gingival index (GI) Loe and Silness, gingival recession, PD, CAL. The last three parameters were assessed for all the teeth and at six locations around the teeth (mesiobuccal, buccal, distobuccal, mesiolingual, lingual, and distolingual). Williams periodontal probe was used for the measurements, and the recordings were rounded to the nearest millimeter. CAL was calculated, considering recession (distance from the cementoenamel junction to the gingival margin) and PD (the deepest probe able point from the gingival margin to the bottom of the pocket). Evaluation of PI was performed in four surfaces of all the teeth (mesial, distal, buccal, and lingual/palatal). BI was measured in four sites (mesial, distal, mid-buccal and mid-palatal/lingual) in all the present teeth. GI index was evaluated on six teeth (Ramfjord teeth).
The participants were randomly and equally allocated to one of the two groups using computer-generated table of random numbers to receive one of the two treatments. The age of the participants was matched in both groups. A blind operator assessed the abovementioned clinical parameters at baseline and 6 weeks after the initial phase of treatment. Strict oral hygiene instructions (OHI) were given to the participants by a single operator who performed the SRP as well. This operator was blind respecting the groups. All the patients received full-mouth supra and subgingival SRP which were performed under local anesthesia. Treatment of the entire oral cavity was done in one session lasting about 1.5–2 h.
After completion of SRP each participant received a package containing the test or placebo medication; all packages were identical in appearance and were marked only with the participant number. Participants in the test group received 2 g tinidazole as loading dose in the 1st day and then 500 mg once daily for 6 days. Participants in the control group received similar looking placebos, with the same dosage, prepared at the Pharmacy College of Shiraz University of Medical Sciences. The treatment groups were masked from the patients, clinical examiner, operator, and statistician.
Three weeks after the first session of the treatment, OHI was reinforced for all the participants and their compliance in the consumption of the drugs was checked too. Anybody who failed to fulfill the oral hygiene and drug usage criteria was removed from the study and another qualified volunteer was substituted. Finally, all the participants in both groups were recalled at 6 weeks after the baseline visit. Clinical parameters, including PI, BI, GI, PD, recession, and CAL, were recorded.
Student's t-test was used for comparing the differences in PI, BI, GI, PD, recession, and CAL between the two groups. To compare the differences in various parameters within each group, paired t-test was used. The level of significance (a) was taken as 0.05, and the confidence intervals were set at 95%. P < 0.05 was considered statistically significant.
| Results|| |
Sixty subjects participated in this double-blind clinical trial study. There were no dropouts during the study; all the subjects completed the trial to the end and returned for the 6-week follow-up visit. The age range of the participants was 25–57 years, with a mean of 42.8 years and standard deviation of 6.84. 52 subjects were male and 8 were female. All the subjects satisfied the inclusion criteria and suffered from moderate to advanced chronic periodontitis. All the subjects were current smokers at the baseline visit with a mean of 7.48 cigarettes smoking per day. Fifty-five percent of the subjects brushed their teeth just once a day and only 15% of them brushed their teeth more than once a day.
In test group, there was significant difference between PD, recession, CAL, PI, BI, and GI in test group after 6 weak interval (P < 001) [Table 1].
|Table 1: Intera group analysis of clinical periodontal parameters from baseline to 6 weeks after therapy|
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In control group also, PD, CAL, PI, BI, and GI showed significant difference after 6 weeks from the baseline visit (P< 001) but there was no significant difference between recession in the control group after 6 weeks interval [Table 1].
The intergroup difference in PD, CAL, PI, and GI was statistically significant 6 weeks after baseline visit (P< 001). It means that the improvements of the periodontal parameters were more in test group. Conversely, there was no significant difference in recession between control and test group after 6 weeks [Table 2].
|Table 2: Intergroup analysis of clinical periodontal parameters from baseline to 6 weeks after therapy|
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| Discussion|| |
This double-blind randomized clinical trial evaluated the clinical effects of tinidazole remedy as an adjuvant to nonsurgical periodontal therapy for the treatment of chronic periodontitis in smokers. The results showed that tinidazole greatly improved the periodontal parameters in comparison to the placebo. These improvements were achieved in a short period, without costly and aggressive interventions. Six weeks after therapy, the smokers who were submitted to SRP plus tinidazole consumption exhibited statistically significant greater reduction in mean PD, GI, BI, and PI and gain in mean CAL compared to the smokers who were submitted to SRP plus placebo. Several studies have shown that SRP alone for the treatment of chronic periodontitis resulted in favorable improvements in the clinical findings., According to these studies, SRP alone resulted in drastic PD reduction and CAL gain. The alterations were dependent on the depth of the pockets. It means that the greatest reduction in PD and gain of CAL was mostly found in the deepest sites., Sbordone et al. exhibited that this improvement in clinical parameters, after SRP alone, did not last long and returned to the baseline values within 2 months. Hence, there have been various assessments to investigate the combination effect of antibiotic therapy and mechanical treatment in the treatment of periodontitis. In the present study, as well, SRP alone improved the periodontal parameters but more significant improvement was achieved by combination of mechanical therapy and tinidazole consumption. In the study conducted by Stelzel and Florès-de-Jacoby also, combined treatment of metronidazole and SRP lead to better resolution of clinical parameters in chronic periodontitis patients compared to mechanical procedure exclusively. Also, Silva et al. showed that the adjunctive use of metronidazole plus amoxicillin offered short-term better clinical and microbiological benefits comparing to SRP alone in the treatment of nonsmokers subjects with chronic periodontitis. In addition, there are other studies that showed the beneficial effect of the addition of antibiotics of the second generation of nitroimidazole derivative group to the conventional mechanical treatment in the therapy of chronic periodontitis patients. For example, Pradeep et al. observed that systematic use of ornidazole, in adjunction to SRP in adults suffering from chronic periodontitis, resulted in significantly better clinical consequences than mechanical periodontal treatment alone. On the contrary, Bono and Brunotto came to this result that there was absence of statistically significant difference between treatment outcomes in two groups of chronic periodontitis patients receiving amoxicillin and metronidazole in adjunction to SRP or mechanical therapy alone. Similarly, Vergani et al. in their pilot study concluded that using systemic metronidazole, in adjunction to SRP, did not lead to additional benefits on microbiological conditions of smokers with chronic periodontitis. As it was mentioned earlier, smoking results in a greater risk for CAL loss, higher number of deep pockets, increased prevalence and severity of vertical defects, and higher counts of some recognized periodontal pathogens. Furthermore, there is modification in the host immune response of smokers and decrease in their capacity to combat pathogens efficiently. Multiple biologic pathways, such as deterioration in neutrophil function, antibody production, local effects of nicotin, differences in the subgingival microbiota, or in the production of inflammatory mediators, have been proposed as the probable causes for the most nonfavorable response to therapy that is observed in smokers with chronic periodontitis when compared to nonsmokers. Taken as a whole smokers display a higher prevalence of edentulism and a greater incidence of tooth loss. Consequently, there has been a variety of efforts to imply new combinational therapies for smokers. Searching for more effective antibiotics with fewer side effects is one of these attempts. Meanwhile, there are different studies that showed the difference between smokers and nonsmokers in their response, both to SRP treatment and antibiotic therapy. According to Faveri et al. and Pahkla et al., the improvements in the clinical and microbial parameters after adjunctive usage of metronidazole plus amoxicillin were less in smokers with chronic periodontitis than in nonsmokers., Also, Dastoor et al. in a pilot study reported that adjunctive systemic azitromycin in combination with periodontal flap surgery did not significantly improve PD reduction or CAL gain in smokers. Albandar declared that there was no sufficient evidence in the literature to support or refute that adjunctive antibiotic therapy would lead to a significant reduction in probing depth and gain in CAL when treating periodontitis in smokers. Also, Palmer et al. confirmed in their study that smokers had poorer clinical response to SRP, regardless of the application of metronidazole. Darby et al. believed that this unfavorable response of smokers to the periodontal treatments may be to the fact that smokers are likely to harbor more periodontal pathogens before and even after the treatment. As well, it has been reported that smokers tend to build up more plaque than nonsmokers. This can be partly the cause of their instability to maintain pocket reduction after successful periodontal treatment.
In the study that was conducted by Sarkiala et al. in 1993, the efficacy of tinidazole in the treatment of periodontitis in dogs was evaluated. In their study, the mean PD was significantly more reduced in tinidazole plus scaling group than in scaling group. Tinidazole is a proficient treatment against anaerobic microorganisms based on its pharmacokinetic characteristics (Cmáx 51 μg/ml, t½ 12.5 h) and has outstandingin vitro activity. Its activity has been shownin vitro against a wide range of anaerobic bacteria and protozoa.
The eliminate rates for Black pigmented anaerobic rod (Porphyromonas gingivalis, Prevotella intermedius, Prevotella melaninogenicus), Fusobacteriums, Prevotella oris, Prevotella oralis, Eubacterium and Actinomyces were 95.8% 94.1%, 83.3% and 76.5%. This anti-bacterial effectiveness of tinidazole against periodontal pathogens was significantly higher than that of metronidazole (P< 0.05). Based on thisin vitro study, it appeared effectual to use tinidazole as local application against periodontal pathogens.
One of the profits of this antibiotic is its long half-life, which allows once a day regimen. There are a number of reasons that favors using tinidazole instead of metronidazole: They have comparable structure and activity, better compliance of tinidazole as a single-dose therapy comparable to 7 days regimen of metronidazole; achievment of higher serum peaks and reproducible tissue concentrations by oral tinidazole, enhanced patient tolerance, less side effects, reduced toxicity and a longer half-life and longer biological life of tinidazole (12–7 h in the case of tinidazole vs. 6–2 h in the case of metronidazole). Also, tinidazole is more lipid soluble than metronidazole, which let it to infiltrate cell membranes more competently. Liew et al. evaluated the concentration of tinidazole in gingival cervical fluid, serum, and gingival tissue in adults with periodontitis, the mean concentration of tinidazole in serum at 24 h was greater than the minimum inhibitory concentration for anaerobic bacteria. These data suggested that a single 2 g oral dose of tinidazole may cause the presence of bactericidal levels of tinidazole for up to 24 h in the periodontal pockets. Based on the previous studies, the dose of tinidazole in the present study was 2 g for the 1st day that was free of toxicity, then 500 mg once daily for 6 days was used to attain compliance. There are few studies comparing the effectiveness of different antibiotics of nitroimidazole group in the treatment of chronic periodontitis. For example, Wang et al. affirmed that the effective rate of tinidazole in patients with periodontitis was 73.1% that was significantly higher than the control group (43.5%) who used metronidazole. They also showed that the ability of tinidazole to kill periodontal main anaerobic bacteria such as Bacteroides gingivalis and Bacteroides melaninogenicus was better than metronidazole.
One limitation of this study was the short follow-up period. It is speculated that after 6 months follow-up period, the improvements in clinical parameters may start to decline.
To the best of our knowledge, this was the first study evaluating the effects of systematic tinidazole as an adjuvant to SRP in the smokers with chronic periodontitis. As long as obtaining satisfying results from periodontal treatment of heavy smokers are usually frustrating, and these patients have less favorable response to both surgical and nonsurgical treatments, investigation for novel combinations in their treatment seems reasonable. Additional long-term, multi-center clinical trials and longitudinal studies should be performed to verify the obtained results from this study.
| Conclusion|| |
Tinidazole may present remarkable characteristics, making it valuable as a candidate for further investigations in the control of anaerobic pathogens involved in different forms of periodontitis. The results of this study showed beneficial effects of systemic tinidazole in the improvement of the clinical periodontal parameters in the smokers with chronic periodontitis.
This paper has been extracted from Ms. ArmaghanTarjan (DDS) thesis which was conducted under supervision of Dr. Farin kiany and advisory of Dr. Fatemeh moludi. The authors would like to thank Dr. Fatemeh Ahmadi for preparing the placebo and Dr. Mehrdad Vossoughi for his assistance in statistical analysis.
Financial support and sponsorship
This study was registered with the Grant No: 8893086 and supported by the International Branch of Shiraz University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]