|Year : 2009 | Volume
| Issue : 2 | Page : 79-84
Effect of a controlled release device containing minocycline microspheres on the treatment of chronic periodontitis: A comparative study
V Gopinath1, T Ramakrishnan2, Pamela Emmadi2, N Ambalavanan2, Biju Mammen2, Vijayalakshmi2
1 Department of Periodontics, Saveetha Dental College and Hospital, Poonamalee High Road, Velapanchavadi, Chennai - 77, India
2 Department of Periodontics, Meenakshi Ammal Dental College and Hospital, Alapakkam Main Road, Maduravoyal, Chennai - 95, India
|Date of Submission||15-Dec-2008|
|Date of Acceptance||09-Jul-2009|
|Date of Web Publication||16-Sep-2009|
Flat C, Lakshmi Apartments, No. 1, Baskara Street, Rangarajapuram, Kodambakkam, Chennai - 24
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Adjunctive therapy with locally delivered antimicrobials has resulted in improved clinical outcomes. The aim of this study was to evaluate the efficacy and safety of locally administered minocycline microspheres (Arestin TM ) in the treatment of chronic periodontitis. Materials and Methods: A total of 60 sites from 15 patients in the age group of 35-50 years, who had periodontal pockets measuring 5-8mm and had been diagnosed with chronic periodontitis, were selected for the study. The selected groups were randomly assigned to either the control group (group A) or the treatment/test group (group B). Only scaling and root planing were done at the base line visit for the control sites followed by local application of Arestin™ (1mg). Clinical parameters such as plaque index, gingival index, and gingival bleeding index were recorded at baseline, day 30, day 90, and day 180 in the selected sites of both the groups. Probing pocket depth also was recorded at baseline, day 90, and day 180 for both the groups. Results: A statistically significant reduction was observed in both groups. Group B showed better results than Group A and these differences were statistically significant. Conclusion: The results of this study clearly indicate that treatment with scaling and root planing plus minocycline microspheres (Arestin™) is more effective and safer than scaling and root planing alone in reducing the signs of chronic periodontitis.
Keywords: Antimicrobial agents, local drug delivery systems, minocycline microspheres (Arestin™), periodontitis
|How to cite this article:|
Gopinath V, Ramakrishnan T, Emmadi P, Ambalavanan N, Mammen B, Vijayalakshmi. Effect of a controlled release device containing minocycline microspheres on the treatment of chronic periodontitis: A comparative study. J Indian Soc Periodontol 2009;13:79-84
|How to cite this URL:|
Gopinath V, Ramakrishnan T, Emmadi P, Ambalavanan N, Mammen B, Vijayalakshmi. Effect of a controlled release device containing minocycline microspheres on the treatment of chronic periodontitis: A comparative study. J Indian Soc Periodontol [serial online] 2009 [cited 2019 Nov 22];13:79-84. Available from: http://www.jisponline.com/text.asp?2009/13/2/79/55844
| Introduction|| |
Periodontal diseases are polymicrobial in nature and the complex interaction among many microbes makes the disease a challenging one to understand and treat. Host inflammatory response to plaque microorganisms causes tissue damage, leading to the destruction of the periodontal tissues in an episodic manner. Bacterial products have the ability to stimulate host cells to secrete a wide variety of inflammatory mediators that have numerous biological activities, some of which cause soft tissue and bone destruction. Cytokines such as tumor necrosis factor- α (TNF- α), interleukin-1β (IL-1β), and inflammatory mediators such as prostaglandin E 2 are known inducers of bone resorption. These are found in high levels in gingival tissues and gingival crevicular fluid of patients with periodontal disease. 
The extent and degree of periodontal destruction varies widely from patient to patient, and in different sites within the same patient. These variations could be due to the presence of complex subgingival populations of microorganisms in different sites. Periodontal diseases are characterized by the presence of periodontal pockets, which are not easily accessible for plaque removal. 
Bacteria in the subgingival area are organized in a complex microbial biofilm. Biofilms are matrix-enclosed bacterial populations that are adherent to each other and/or surfaces or interfaces. These microbial plaques are extraordinarily persistent, difficult to eliminate, and play a vital role in periodontal disease.  Physical disruption of microbial plaque through hand or powered instrumentation is an effective way of eliminating biofilms. However, reinfection of periodontal pockets from recolonization of putative bacteria can occur within 60 days after mechanical therapy. 
Successful treatment is dependent on halting tissue destruction through the elimination or control of etiological agents, together with microbial shift towards one typically present in health. Mechanical therapy alone may fail to eliminate invasive, pathogenic bacteria because of their location within the gingiva and dental tissues, which are inaccessible to periodontal instruments. Treatment strategies aiming primarily at suppressing or eliminating specific periodontal pathogens include local and systemic administration of antibiotics.  In order to obtain an effective concentration of the antimicrobial drug which would reach the microorganisms in the periodontal tissues after systemic administration, repeated intake is required over a prolonged period of time.
One of the biggest benefits of any locally delivered drug is that it does not require patient compliance for regular drug intake. The clinician places the drug which releases the antimicrobial for an extended period of time at a steady pharmacological level.  Another advantage of a locally delivered drug is that it can be placed adjacent to disease sites in the periodontium, leaving other parts of the body unaffected. 
Arestin™ is made up of minocycline, a semi-derivative of tetracycline, and a very potent broad-spectrum antibiotic. Minocycline has significant antimicrobial activity against a wide range of organisms as well as an anticollagenase effect. Minocycline works by interfering with protein synthesis in the bacterial cell wall.
Arestin™ delivers minocycline in a powdered microsphere delivery system. The microspheres have diameters ranging from 20 to 60 µ. The active ingredient is minocycline hydrochloride which exists as particles distributed throughout the interior of the microspheres. When Arestin™ is administered, it immediately adheres to the periodontal pocket. 
Gingival crevicular fluid hydrolyzes the polymer, causing water-filled channels to form inside the microspheres. These holes provide escape routes for the encapsulated antibiotic for sustained release. The active drug dissolves and diffuses out of the microspheres through the channels into the surrounding tissues. After ten days, the microspheres are fragmented and continue to release minocycline for 14 days or longer; eventually, these microspheres completely bioresorb.
Traditional therapies such as tooth brushing, flossing, subgingival irrigation, and mechanical debridement are successful for patients with mild periodontal diseases. However, as the periodontal pocket deepens, the patient's home care procedures as well as professional debridement loses effectiveness, making local drug delivery a viable option. The addition of local delivery can also help to maintain or control the disease between maintenance visits. 
The purpose of this study was to compare the clinical effects of scaling and root planing with those of scaling, root planing, and local administration of minocycline hydrochloride (1mg) (Arestin™) delivered subgingivally in patients with chronic periodontitis.
| Materials and Methods|| |
A total number of 15 patients aged 35-50 years diagnosed with chronic periodontitis and having probing depths ranging from 5 to 8mm as well as radiographic evidence of bone loss, were selected for the study from the Department of Periodontics, Meenakshi Ammal Dental College and Hospitals, Chennai. Ethical approval was obtained from the Institutional ethical committee for the study.
Inclusion criteria for patient selection.
Patients in the age group of 35-50 years.
Patients diagnosed as suffering from chronic periodontitis having a probing pocket depth of 5 to 8mm with radiographic evidence of alveolar bone loss and without mobility of teeth.
Patients willing to take part in the study and maintain appointments regularly.
Exclusion criteria for patient selection.
Patients having systemic diseases like diabetes mellitus, hypertension, bleeding disorders, hyperparathyroidism.
Pregnant women and lactating mothers.
Patients allergic to tetracyclines.
Patients who have had periodontal treatment in last six months.
Antibiotic therapy within three months prior to treatment.
Long-term therapy within a month prior to enrollment with medications that could affect periodontal status or healing.
Patients with medical or dental therapy scheduled or expected to occur during the course of this study that could have an impact on the subjects ability to complete the study.
A total number of 60 sites from 15 patients were selected for the study. The duration of the study was for six months. Four sites were identified for the study in each patient: Two sites served as control sites (Group A) and two sites on the contralateral side served as test sites (Group B). For all patients, general, oral and full mouth periodontal examination was carried out and informed consent was obtained from the patients. On screening day (day 0), patient evaluation was followed by impressions for the fabrication of acrylic stents required for the measurement of pocket depths in the control and test sites during the study period [Figure 1]. Variables associated were recorded on baseline day (day 0) before treatment to provide baseline data.
The following parameters were recorded:
- Plaque index 
- Gingival index 
- Gingival bleeding index 
- Probing pocket depth 
The control and test sites were grouped and treated as follows:
Group A (control) - Comprised of 30 sites; only scaling and root planing was done at the baseline visit.
Group B (test) - Comprised of 30 sites; scaling and root planing was followed by local application of Arestin™ (1mg) at the baseline visit.
Both the control and test sites were again examined on the 30 th day. During this visit, all clinical parameters, except probing depth, were measured. An additional application of Arestin™ (1mg) was given in the test sites,. The control and test sites were also examined on the 90 th and 180 th days, and all clinical parameters including probing pocket depth were recorded.
Application of minocycline microspheres [Figure 2].
After insertion of the local drug delivery system, the patients were advised not to eat hard food that could traumatize the gingiva. They were also advised not to brush the area for 12 h or to floss or use interproximal cleaning devices for ten days. During the study period, the patients were instructed to continue regular tooth brushing and interdental cleansing. They were also instructed not to use any mouth washes for the duration of the study.
Means and standard deviations were estimated from the samples for each study group. Mean values were compared by Student's independent t-test/Student's paired t-test wherever appropriate. The proportion of positivity of the gingival bleeding index was compared between control and test groups by Pearson's chi-square test with Yate's continuity correction/Fisher's exact test (two-tailed) wherever appropriate. In the present study, P < 0.05 was considered as the level of significance.
| Results|| |
The mean reduction in the plaque index score in group A from day 0 to day 30 was 0.46 ± 0.43, 0.42 ± 0.42 from day 0 to day 90, and 0.53 ± 0.39 from day 0 to day 180, all statistically significant differences (P < 0.0001).The mean reduction in the gingival index score in group A was 0.23 ± 0.35 from day 0 to day 30, 0.28 ± 0.50 from day 0 to day 90, and 0.38 ± 0.49 from day 0 to day 180, all statistically significant differences (P < 0.0001). The mean reduction in probing pocket depth values for group A was 0.24 ± 1.07 from 0 to day 90, 0.37 ± 1.08 from day 0 to day 180, a difference that was not statistically significant. The mean reduction in plaque index scores in group B from day 0 to day 30 was 0.56 ± 0.45, 0.72 ± 0.32 from day 0 to day 90, and 0.78 ± 0.32 from day 0 to day 180, all statistically significant differences (P < 0.0001).The mean reduction in gingival index scores in group B was 0.72 ± 0.55 from day 0 to day 30, 0.80 ± 0.41 from day 0 to day 90, and 0.95 ± 0.49 from day 0 to day 180, all statistically significant differences (P < 0.0001). The mean reduction in probing pocket depth for group B was 1.73 ± 0.87mm from 0 to day 90, and 1.66 ± 0.96mm from day 0 to day 180, again a statistically significant difference (P < 0.0001) [Table 1].
[Table 2] shows that there was no statistically significant differences in the mean plaque index scores between groups A and B on days 0 and 30. There was a statistically significant difference in the mean plaque index on days 90 and 180 between the two groups. The mean reduction in plaque index scores and the percentage of reduction were also statistically significant between days 0 and 90 and between days 0 and 180 [Graph 1]- [Additional file 1].
[Table 3] reveals that there was no statistically significant difference in the mean gingival index between groups A and B on day 0. However, there was a statistically significant difference in the mean gingival index on days 30, 90, and 180 between the two groups. The mean reduction in gingival index scores and the percentage of reduction were also statistically significant between days 0 and 30, days 0 and 90, and between days 0 and 180 [Graph 2]- [Additional file 2].
[Table 4] shows that on day 0, there was bleeding on probing of all sites of Groups A and B. On day 30, there was a 60% reduction in bleeding from the sites in group A and 80% reduction in bleeding from sites in group B. On day 90, there was a 63.4% reduction in bleeding of the sites in group A and 83.3% reduction in bleeding from sites in group B. On day 180, there was a 66.7% reduction in bleeding from sites in group A and 90% reduction in bleeding from sites in group B (P < 0.0001). The reduction in bleeding on probing was significant in both groups A and B. The reduction in group B was significantly higher than the reduction seen in group A on the 30 th day, 90 th day, and 180 th day.
[Table 5] reveals that there was no statistically significant difference in the mean probing pocket depth between the two groups on day 0. On days 90 and 180, the difference in the mean probing pocket depth was statistically significant between the two groups (P < 0.0001). The mean reduction in probing pocket depth between days 0 to 90 and days 0 to 180 was statistically significant between the two groups (P < 0.0001).
| Discussion|| |
In our study, no statistically significant difference was observed between the two groups on the 30 th day from the baseline, but there was a significant difference in the plaque index on the 90 th and 180 th days between the two groups [Table 1]. These findings are in consistent with the those of the earlier studies done by Vansteenberghe et al.,  Mullur et al.,  Saito et al.,  Jones et al.,  Timmerman et al.,  Hagiwara et al.,  and Vansteenberghe et al. 
In our study, the mean reduction in plaque index scores between days 0 and 30 for groups A and B was not statistically significant [Graph 1]. However, the mean reduction in plaque index scores between day 0 and day 90 and between day 0 and day 180 for Group A and Group B was statistically significant [Table 2]. The mean reduction in gingival index scores between days 0 and 30, between days 0 and 90, and between days 0 and 180 for Groups A and B were all statistically significant [Table 3]. Thus, when the gingival status was compared between Group A and Group B, a significant improvement was observed on day 30, day 90, and day 180 in the test sites [Graph 2]. This is consistent with the findings of the studies conducted by Muller et al.,  Vansteenberghe et al.,  Saito et al.,  Jones et al.,  Timmerman et al.,  Radvar et al.,  Hagiwara et al.,  Vansteenberghe et al.,  and Kinane et al. 
When group A and group B were compared, a reduction in bleeding was seen from the sites in both the groups, but the percentage of reduction in bleeding from the sites was more in group B compared to sites of group A [Table 4]. This was statistically significant and consistent with the findings of Vansteenberghe et al.,  Vansteenberghe et al.,  by Mullur et al.,  and Timmerman et al. 
A significant reduction in probing pocket depth was found in group B when compared with group A [Table 5]. This was in accordance with the studies conducted by Mullur et al.,  Vansteenberghe et al.,  Saito et al.,  Jones et al.,  Timmerman et al.,  Radvar et al.,  Makoto Umeda et al.,  Hey-Riyeom,  Hagiwara et al.,  Vansteenberghe et al.,  Kinane et al.,  Williams et al.,  Dean et al.,  and Greenstein et al. 
The above results show that scaling and root planing plus Minocycline microspheres provide significantly greater probing depth reduction than scaling and root planing alone. This significant change in all the clinical parameters examined in the test group, is because Arestin™ releases therapeutic doses of the drug for more than 14 days, well above the minimum inhibitory concentration needed to kill most putative pathogens for periodontal disease.  A pharmacokinetic study of minocycline also revealed mean dose saliva levels approximately 1,000 times higher than those in serum. This finding suggests that minocycline has minimal absorption through the periodontal pocket into serum and stays concentrated in saliva. In addition, levels of minocycline were found in saliva for longer than 14 days, suggesting a sustained release of minocycline from the local delivery system.  It may be concluded that Arestin™ (1mg Minocycline microspheres) delivered in a biodegradable delivery system, proves to be an effective means of reducing the clinical signs of chronic periodontitis.
| Conclusion|| |
From the results of the study, the following conclusions can be drawn:
Test sites where Minocycline microspheres were employed, displayed a statistically significant reduction in all the clinical parameters (Plaque index, Gingival index, Gingival bleeding index, Probing pocket depth) after treatment as compared to control sites, which showed only minimal changes.
A degradable, subgingivally placed drug delivery system containing 1mg Minocycline microspheres, is a safe and efficient adjunct to scaling and root planing in the treatment of chronic periodontitis.
The results of this study confirm that Minocycline microspheres are a safe and efficient adjunct to scaling and root planing, and can produce significant clinical benefits when compared to scaling and root planing alone.
| Acknowledgment|| |
Dr. Asvin Vasanthan, BDS, DDS, MS, Clinical Assistant Professor, Department of Periodontics, University of Missouri, Kansas City, USA.
| References|| |
|1.||Shapira L, Houri Y, Barak V, Halabi A, Soskolne WA, Stabholz A. Human Monocyte response to cementum extracts from diseased teeth: Effect of conditioning with tetracycline. J Periodontol 1996:67:682-7. |
|2.||Lindhe J, Nyman S. Clinical trials in periodontal therapy. J Periodontal Res 1987:27:217-21. |
|3.||Williams RC, Paquette DW, Offenbacher S, Adams DF, Armitage GC, Bray K, et al. Treatment of periodontitis by local administration of minocycline microspheres: A controlled trial. J Periodontol 2001;72:1535-44. |
|4.||Sbordone L, Ramaglia L, Gulletta E, Iacono V. Recolonization of the subgingival microflora after scaling and root planing in human periodontics. J Periodontol 1990;61:579-84. |
|5.||O'Leary K, Barrington EP, Gottsegen R. Periodontal therapy. A summary status report 1987-1988. J Periodontol 1988;59:539-49. |
|6.||Wilder RS. Treating chronic periodontitis with the local delivery of minocycline microspheres. Contemporary oral hygiene Jan/Feb 2002 |
|7.||Maehara R, Hinode D, Terai H, Sato M, Nakamura R, Matsuda N, et al. Inhibition of bacterial and mammalian collagenolytic activities by tetracyclines. Nippon Shishubyo Gakkai Kaishi 1998;30:182-90. |
|8.||Greenstein G, Polson A. The role of local drug delivery in the management of periodontal disease: A comprehensive review. J Periodontol 1998;69:507-20. |
|9.||Carranza FA, Newman MG. Clinical periodontology. 8 th ed. 1996. p. 64-8,355-6. |
|10.||Van Steenberghe D, Bercy P, Kohl J, De Boever J, Adriaens P, Vanderfaeille A, et al. Subgingival minocycline hydrochloride ointment in moderate to severe chronic adult periodontitis: Arandomized, double-blind, vehicle controlled, multicenter study. J Periodontol 1993;64:637-44. |
|11.||Müller HP, Lange DE, Müller RF. A 2 year study of adjunctive Minocycline HCl in Actinobacillus Actinomycetem Comitans associated periodontitis. J Periodontol 1993;64:509-19. |
|12.||Saito A, Hosaka Y, Nakagawa T, Seida K, Yamada S, Okuda K. Locally delivered minocycline and Guided Tissue Regeneration to treat post juvenile periodontitis: A case report. J Periodontol 1994;65:835-9. |
|13.||Jones AA, Kornman KS, Newbold DA, Manwell MA. Clinical microbiologic effects of controlled release locally delivered minocycline in periodontitis. J Periodontol 1994;65:1058-66. |
|14.||Timmerman MF, Van der weijden GA, Van steenbergen TJ, Mantel MS, de Graaff J, Van der velden U. Evaluation of the long term efficacy and safety of locally applied minocycline in adult periodontitis patients. J Clin Periodontol 1996;23:707-16. |
|15.||Hagiwara S, Takamatsu N, Tominaga Y, Umeda M. Subgingival distribution of periodontopathic bacteria and their susceptiblitiy to minocycline HCL. J Periodontol 1998;69:92-9. |
|16.||Van Steenberghe D, Rosling B, Söder PO, Landry RG, Van der velden U, Timmerman MF, et al. A 15 month evaluation of the effects of repeated subgingival minocycline in chronic adult periodontitis. J Periodontol 1999;70:657-67. |
|17.||Müller HP, Lange DE, Müller RF. Failure of adjunctive minocycline HCL to eliminate oral Actinobacillus Actinomycetem Comitans. J Clin Periodontol 1993;20:498-504. |
|18.||Radvar M, Pourtaghi N, Kinane DF. Comparison of 3 periodontal local antibiotic therapies in persistent periodontal pockets. J Periodontol 1996;67:860-5. |
|19.||Kinane DF, Radvar M. A six month comparison of three periodontal local antimicrobial therapies in persistent periodontal pockets. J Periodontol 1999;70:1-7. |
|20.||Umeda M, Tominaga Y, He T, Yano K, Watanabe H, Ishikawa I. Microbial flora in the acute phase of periodontitis and the effect of local administration of minocycline. J Periodontol 1996;67:422-7. |
|21.||Yeom HR, Park YJ, Lee SJ, Rhyu IC, Chung CP, Nisengard RJ. Clinical and microbiological effects of minocycline loaded microcapsules in adult periodontitis. J Periodontol 1997;68:1102-9. |
|22.||Dean JW, Branch-Mays GL, Hart TC, Reinhardt RA, Shapiro B, Santucci EA, et al. Topically applied minocycline microspheres: Why it works. Compend Contin Educ Dent 2003;24:247-50, 252-7. |
|23.||Greenstein G. The effect of minocycline microspheres in the treatment of chronic periodontitis: Statistical Vs clinical significance. Compend Contin Educ Dent 2003;24:121-30. |
|24.||Christersson LA. Tissue response and release of minocycline after subgingival deposition by use of resorbable polymer. Warminster, PA: Ora pharma,Inc; 1998. |
|25.||Paquette D, Minsk L, Lessam J. A pharmacokinetic study of a locally delivered minocycline therapeutic system (MPTS). J Clin Periodont 2000;27:27. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]