Journal of Periodontology; Copyright 2015
DOI: 10.1902/jop.2015.150161
Adjunctive Local Delivery of Aloe Vera Gel in Type 2 Diabetics With Chronic Periodontitis : A Randomized Controlled Clinical Trial Dr. A R Pradeep MDS*, Dr. Vibhuti Garg BDS (MDS)*, Dr. Arjun Raju MBBS (MD)†, Dr. Priyanka Singh MBBS (MS)‡ *Department of Periodontology, Government Dental College and Research Institute, Bengaluru-560002, Karnataka, India. †
‡
Department of Radio-diagnosis, Uttarakhand Government Medical College, Haldwani (Nainital – 263129), Uttarakhand, India.
Department of Ophthalmology, Grant Medical College & JJ Group of Hospitals, JJ Marg, Nagpada-Mumbai Central, Off Jijabhoy Road, Mumbai-400008, Maharashtra, India.
BACKGROUND: Herbal agents, like Aloe vera (AV), have been in use for both medical and dental therapy since historical times. AV has anti-inflammatory, antioxidant, antimicrobial, hypoglycaemic, healing promoting and immune boosting properties. This study is aims at investigating the clinical effectiveness of locally delivered AV gel used as an adjunct to scaling and root planing (SRP) in the treatment of type 2 DM patients with chronic periodontitis (CP). MATERIAL AND METHODS: Sixty patients with probing depth (PD) ≥5mm and clinical attachment (CA) level ≥3mm were randomly divided into two groups. All patients underwent SRP. Placebo gel was locally delivered in Group 1 patients and AV gel in Group 2 patients. Clinical recording of full mouth plaque index (PI), modified sulcus bleeding index (mSBI), probing depth (PD) and clinical attachment (CA) level was done first at baseline and then at intervals of 3 months and 6 months. RESULT: Patients in AV group showed significantly greater mean reductions in PI, mSBI and PD and mean gain in CA level compared to those in placebo group from baseline to 3 months. Gain in CA level was significantly greater in AV group at all time intervals than the placebo group. CONCLUSION: Adjunctive use of AV gel LDD, in comparison to placebo gel LDD, is associated with greater reduction in PI, mSBI and PD as well as more gain in CA level in type 2 diabetics with CP.
KEY WORDS: Chronic periodontitis; dental scaling; regeneration; aloe.
Chronic periodontitis (CP) is inflammation of periodontium induced by microbes leading to gingival inflammation, periodontal tissue destruction and alveolar bone loss.1 Host response to infection, rather than the infectious agent itself, is the cause of most of the tissue damage in periodontal disease.2 This involves innate immune response activation with upregulation of monocytes/polymorphonuclear leukocyte-derived proinflammatory cytokines and downregulation of macrophage-derived growth factors.3 Symbiosis between diabetes and periodontitis is evident in the poor glycaemic control seen in CP patients and increased prevalence and severity of periodontitis seen in diabetic patients.4 Periodontitis has indeed been identified as the sixth complication of diabetes mellitus (DM).5 Periodontal therapy encompasses a broad range of treatment modalities, including nonsurgical periodontal therapy (NSPT), such as scaling and root planing (SRP) alone or with adjunctive administration of systemic or local antimicrobial/anti-inflammatory agents and surgical (resective and/or regenerative) periodontal therapy.6 Traditionally, dental practitioners have depended on mechanical debridement (SRP) in managing periodontal infections.7 However, it is associated with a high rate of recurrence of
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DOI: 10.1902/jop.2015.150161
periodontal disease7 and may fail to reduce or eliminate the anaerobic infection at the base of the pocket, inaccessible areas like the furcation, within the gingival tissues and structures inaccessible to periodontal instrumentation like in sites with probing depths exceeding 5mm.8 An effective adjunct would be local drug delivery (LDD) systems, which provide controlled release of the therapeutic agent at specific subgingival sites, thus translating into high concentrations at the target site with reduced dosage, fewer side effects compared to systemic drugs, fewer applications and high patient acceptance.9,10 Systemic administration, though found to be effective in treating periodontal pockets, requires prolonged repeated administration of a relatively high dose to achieve the required sulcular concentrations, thus raising the chances of pathogens developing resistance and commensal flora being altered with host expressing adverse effects like allergic/ anaphylactic reaction, gastric disturbances, superinfection, nausea, vomiting, etc.11 Since historical times, various herbal and natural products have been used for chemotherapeutic purposes in the field of medicine and dentistry, with the advantage of fewer side effects and cost-effectiveness.12 Aloe vera (AV) is one such medicinal, perennial succulent plant belonging to the Liliaceae Family, with anti-inflammatory,13 antioxidant,14 antibacterial,15 antiviral,16 antifungal17 and immune boosting properties.18 It also promotes wound healing by accelerating epithelial cell migration and collagen maturation, facilitating tissue restoration.19 Acemannan, a polysaccharide from AV, has also been found to have osteogenic properties.20 AV has also shown hypoglycemic and hypolipidemic effects in noninsulin dependent diabetics, causing significant reduction in blood glucose levels, blood pressure and lipid profile of the diabetic patients.21 In view of these properties, local delivery of AV may be evaluated for its usefulness in the treatment of inflammatory diseases like CP,1 especially those aggravated by type 2 DM.4 The novel use of this herbal product may serve to widen the treatment options for CP deteriorated by DM. Till date, we have not come across any study evaluating the clinical effects of locally delivered (LD) AV gel in type 2 diabetics with CP. Hence, the present study was designed to evaluate the clinical affects of LD AV gel and compare it with LD placebo gel as an adjunct to SRP in type 2 diabetics with CP.
MATERIALS AND METHODS Source of Data This was a single-centre, randomized, longitudinal, triple masked, interventional study, the patients for which were selected from the outpatient section of the Department of Periodontology, Government Dental College and Research Institute (GDCRI), Bengaluru. Sixty patients (33 males and 27 females), aged 25 to 45 years (mean ± SD = 34.76 ± 5.15 years) with a diagnosis of CP and type 2 DM, voluntarily enrolled in this study, after providing a written informed consent. The Ethical Committee, GDCRI, Bengaluru provided the ethical clearance for the study. The period of study was from June 2014 to December 2014 (ClinicalTrials.gov Identifier: NCT02386020). Selection Criteria Patients with well-controlled type 2 DM (selected according to American Diabetes Association criteria 2013)22 and CP with moderate to deep pockets [probing depth (PD) ≥5mm23 and clinical attachment (CA) loss ≥3mm24] without any history of periodontal or antibiotic therapy in past 6 months were included. Exclusion criteria were: presence of any other known disease/condition or intake any medication that can affect the periodontal status,
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allergy (known or suspected) to herbal medications, systemic antimicrobial therapy, aggressive periodontitis, smoking, alcoholism, immunocompromised state and pregnant or lactating females. Patients were selected based on these criteria (by VG) and coin toss was used to randomly allocate 30 patients to each treatment group. One site per patient, i.e. the site with the maximum PD and CA loss and with bleeding on probing (BOP), received SRP at baseline until the root surfaces appeared clean and smooth, followed by LDD of placebo gel (in group 1) or AV in situ gel (in group 2) (by VG). No medications (such as antibiotics, anti-inflammatory or antiplaque agents) were prescribed after treatment. Clinical parameters, including modified sulcus bleeding index (mSBI),25 full-mouth and site-specific plaque index (PI),26 PD and clinical attachment (CA) level, were recorded at baseline (before SRP) and at 3 and 6 months after LDD. A custom-made acrylic stent and a University of North Carolina (UNC) no.15 color-coded periodontal probe§ were used to standardize the measurement of PD and CA level. CA loss was calculated by measuring the distance from the stent (apical extent) to the base of the pocket minus the distance from the stent to the cemento-enamel junction (CEJ). Treatment to both the groups was provided by a single clinician (VG) and all the pre- and post-treatment clinical measurements were recorded by another examiner (ARP), who was masked to the type of treatment received by the patients. The adjusted mean at each visit is shown in Tables 2. Intra-Examiner Calibration Before beginning the study, 20 patients were examined twice, 24 hours apart. If the difference between the measurements made at baseline and after 24 hours was within 1 mm at the 95% level, intra-examiner calibration was accepted. Formulation of AV in Situ Gel After intensive in vitro investigations for optimization and stability, the AV gel was developed at the Government College of Pharmacy, Bengaluru, following the procedure described by Velam et al.27 The central parenchymatous pulp from aloe leaves was washed repeatedly with water and finally with 0.1N sodium hydroxide (NaOH). The treated pulp was placed in a blender to obtain the juice. This juice was prefiltered using a cotton bed and then patiented to repeated vacuum filtration until a clear liquid was obtained. To this, 1% w/w carbopol 934 and 0.5% w/w methyl paraben were added and dispersed uniformly. Carbopol gellifies under alkaline conditions. A 0.5N NaOH solution was added dropwise using moderate agitation until a gel was formed. The prepared AV gel was weighed and stored in air tight containers in a dark room to prevent photooxidation.27 Both, AV gel and placebo gel were prepared similar in color and consistency so as not to affect the examiners blinding. Local Drug Delivery For standardization, a blunt cannula was used to deliver 0.1 ml of the prepared placebo or gel into the periodontal pockets at the control/test site, respectively. After delivery, the viscosity of the prepared formulation decreased, swelling up and occluding the periodontal pocket, precluding the need for placement of periodontal dressing. After in situ gel placement, patients were instructed to avoid brushing or using any interdental aids near the treated areas or chewing hard or sticky foods, for 1 week. At the recall visits, supragingival deposits, if any, were removed and adverse effects, if any, were noted.
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Statistical Analysis: The data were analyzed using a SPSS statistical software program.ǁ Before initiating the study, sample size was determined by power calculations. The primary outcome measure was the difference between the groups in mean CA level change from baseline to the end of follow-up. To achieve a 90% statistical power, an unpaired t-test suggested inclusion of minimum 25 patients in each group (assuming an α-error=0.05 and an expected withdrawal/dropout rate of 15%). The results were averaged for each clinical parameter at baseline, 3 and 6 months. Shapiro-Wilk's W test was employed to test the normality assumption of the data. The mean changes in the parameters were calculated from baseline to 3 and 6 months. For all clinical parameters, the significance of inter-group differences were assessed using analysis of variance (ANOVA) test. Repeated measure ANOVA was used to evaluate the statistical significance of mean change from baseline to follow-up visits within the groups. A t-test was employed to determine the significance of differences between the groups and p values 0.05) (Table 2). Within each group, the mean changes for all the parameters were significant at all intervals (Table 3). Inter-group comparison (Table 4) shows that there was a significantly greater mean reduction in all parameters from baseline to 3 months in the AV group than the placebo group. AV group also showed significantly greater mean reduction in PI and mSBI in the 3-6 months interval as well as in PD from baseline to 6 months. Mean gain in CA level was significantly greater in the AV group at all time intervals than the placebo group.
DISCUSSION Periodontitis and DM have a bidirectional relationship.28 Periodontal infection is associated with transient bacteremias due to breach in periodontal attachment integrity.29 These bacteria and their toxins pose a systemic challenge, linking periodontitis to hyperinflammatory response state and metabolic dysregulation in diabetes.29 Accumulation of advanced glycation end products (AGEs) in diabetes induces an exaggerated monocytic inflammatory response, resulting in exaggerated secretion of local and systemic inflammatory mediators mediating periodontal tissue destruction.29 The severity and incidence of progressive periodontal disease is increased two to three fold in diabetics,28 in association with impaired collagen generation and exaggerated collagenase activity.30 Moreover, blood glucose levels have been found to be higher in periodontitis patients and in diabetic rats with experimental periodontitis.31 Thus, improvement in metabolic control can be achieved by effective periodontal therapy in of type 2 diabetes. A meta-analysis by Sun et al32 revealed that periodontal treatment could decrease HbA1c levels and improve glycemic status in type 2 diabetics with periodontal diseases.
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Conventional non-surgical periodontal therapy is based on the elimination of foci of infections by mechanical debridement, including SRP, as well as local drug delivery (LDD) of therapeutic agents, such as herbal products, into periodontal pockets. Use of medicinal herbs or their extracts are effective in preventing and treating oral conditions.33 Aloe vera is one such herbal plant, used in dentistry for the treatment of oral lichen planus,34 burning mouth syndrome,35 gingivitis36 and periodontal diseases.37 The current study clinically evaluated the adjunctive use of AV gel with SRP for the treatment of type 2 diabetics with CP and found the improvement in clinical parameters to be significantly more with AV compared to placebo gel. Significant reduction in full mouth PI can be explained by antibacterial effect of AV on periodontal bacteria.15,38 There was also a significant reduction in mSBI, which can be attributed to the anti-inflammatory13 and antibacterial38 properties of AV. AV also accelerates collagen synthesis and promotes wound healing,19 that can account for the significant PD reduction and significant CA level gain. Gain in CA level was significantly higher with AV LDD at all time intervals, suggesting regenerative potential of this herbal agent. The mean reduction in PI and mSBI and the mean CA level gain was significantly greater in AV group in the 3-6 months interval, suggesting long term benefits of this local delivery system. These findings are in accordance with those of Abdelmonem et al,37 who found AV LDD as an adjunct to mechanical periodontal therapy to be associated with significant improvement in microbiologic as well as clinical outcomes in CP patients. In our previous study, we found that toothpaste containing AV was effective in reducing the microbial colonies of S. sangius, S. oralis, Actinomyces viscosus and Actinomyces naeslundii in patients with chronic gingivitis.39 Hence, local delivery of AV may be associated with even greater reduction of these periopathogens. The above-mentioned properties, along with the ease of availability, no known adverse effects and cost effectiveness make AV an ideal candidate for treatment of immune-inflammatory conditions like CP in type 2 diabetics. Considering these facts, direct subgingival delivery of AV as an adjunct to SRP can be proposed as a better approach for treatment of periodontal pockets in type 2 diabetics with CP compared to SRP with or without placebo gel LDD. Further, multi-center, long term, double blinded, randomized clinical trials with glycaemic status assessment, histological bone gain evaluation and microbiologic profile determination are needed to confirm the findings in this study.
CONCLUSION: It can thus be demonstrated from this clinical trial that AV gel, delivered locally into periodontal pockets, as an adjunct to SRP, in type 2 diabetics with CP, stimulated a significant improvement in clinical parameters as compared to placebo gel. Thus, use of complementary and alternative medicine can provide new therapeutic options in patients who are at greater risk for periodontal destruction. ACKNOWLEDGEMENTS: We would like to express our gratitude to Sneha Pharmaceuticals, Bengaluru, India for providing us samples of AV as well as to Prof. B.G Shivananda, Principal, Government College of Pharmacy, Bangalore, India for his help in the preparation the LDD gels.
DISCLOSURE: The authors declare that they have no conflict of interests. Authors declare no financial support or relationships that may pose conflict of interest.
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REFERENCES: 1.
Socransky SS, Haffajee AD. The bacterial etiology of destructive periodontal disease: current concepts. J Periodontol 1992;63:322–331.
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Van Dyke TE, Lester MA, Shapira L. The role of the host response in periodontal disease progression: implication for future treatment strategies. J Periodontol 1993;64:792–806.
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Offenbacher S, Odle BM, Van Dyke TE. The use of crevicular fluid prostaglandin E2 levels as a predictor of periodontal attachment loss. J Periodontal Res 1986;21:101–112.
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Bascones-Martínez A, Arias-Herrera S, Criado-Cámara E, Bascones-Ilundáin J, Bascones-Ilundáin C. Periodontal disease and diabetes. Adv Exp Med Biol 2012;771:76-87.
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Loe H. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 1993;16:329-334.
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Heitz-Mayfield LJ, Lang NP. Surgical and nonsurgical periodontal therapy. learned and unlearned concepts. Periodontol 2000 2013;62:218-231.
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Slots J, Jorgensen MG. Effective, safe, practical and affordable periodontal antimicrobial therapy: where are we going, and are we there yet? Periodontol 2000 2002;28:298-312.
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Stambaugh RV, Dragoo M, Smith DM, Carasal L. The limits of subgingival scaling. Int J Periodontics Restorative Dent 1981;1:30-41.
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Greenstein G. Local drug delivery in the treatment of periodontal diseases: assessing the clinical significance of the results. J Periodontol 2006;77:565-578.
10. Soskolne WA. Subgingival delivery of therapeutic agents in the treatment of periodontal diseases. Crit Rev Oral Biol Med 1997;8:164-174. 11. The Research, Science and therapy Committee of the American Academy of Peridontology, Slots J. Systemic Antibiotics in Periodontics (Position paper). J Periodontol 2004;75:1553-1565. 12. Sharma R, Hebbal M, Ankola AV, Murugaboopathy V, Shetty SJ. Effect of two herbal mouthwashes on gingival health of school children. J Tradit Complement Med 2014;4:272-278. 13. Davis RH, Rosenthal KY, Cesario LR, Rouw GA. Processed aloe vera administered topically inhibits inflammation. J Am Podiatr Med Assoc 1989;79:395–397. 14. Yagi A, Kabash A, Okamura N, Haraguchi H, Moustafa SM, Khalifa TI. Antioxidants, free radical scavenging and anti-inflammatory effects of aloesin derivatives in aloe vera. Planta Med 2002;68:957–960. 15. Lorenzetti LJ, Salisbury R, Beal JL, Baldwin JN. Bacteriostatic property of aloe vera. J Pharma Sci 1964;53:1287. 16. Saoo K, Miki H, Ohmori M, Winters WD. Antiviral activity of aloe extracts against cytomegalovirus. Phytother Res 1990;10:348–350. 17. Rosca-Casian O, Parvu M, Vlase L, Tamas M. Antifungal activity of aloe vera leaves. Fitoterapia 2007;78:219–222. 18. Fani M, Kohanteb J. Inhibitory activity of aloe vera gel on some clinically isolated cariogenic and periodontopathic bacteria. J Oral Sci 2012;54:15-21. 19. Dat AD, Poon F, Pham KB, Doust J. Aloe vera for treating acute and chronic wounds. Cochrane Database Syst Rev 2012;2:CD008762. 20. Sierra-García GD, Castro-Ríos R, González-Horta A, Lara-Arias J, Chávez-Montes A. Acemannan, an extracted polysaccharide from aloe vera: A literature review. Nat Prod Commun 2014;9:1217-21. 21. Choudhary M, Kochhar A, Sangha J. Hypoglycemic and hypolipidemic effect of aloe vera L. in non-insulin dependent diabetics. J Food Sci Technol 2014;51:90–96. 22. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2013;36:S67-S74. 23. Heitz-Mayfield LJ, Lang NP. Surgical and nonsurgical periodontal therapy: learned and unlearned concept. Periodontol 2000 2013;62:218-231.
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24. Flemmig TF. Periodontitis. Ann Periodontol 1999;4:32-8. 25. Mombelli A, van Oosten MA, Schurch E, Lang NP. The microbiota associated with successful or failing implants. Oral Microbiol Immunol 1987;2:145-151. 26. Silness J, Loe H. Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 1964;22:121-135. 27. Velam V, Yalavarthi PR, Sundaresan C. In vitro and in vivo assessment of piroxicam incorporated aloe vera transgel. Int J Pharm Investig 2013;3:212–216. 28. Taylor GW. Bidirectional interrelationships between diabetes and periodontal diseases: an epidemiologic perspective. Ann Periodontol 2001;6:99-112. 29. Southerland JH, Taylor GW, Moss K, Beck JD, Offenbacher S. Commonality in chronic inflammatory diseases: periodontitis, diabetes and coronary artery disease. Periodontol 2000 2006;40:130–143. 30. Reynolds JJ, Meikle MC. Mechanisms of connective tissue matrix destruction in periodontitis. Periodontol 2000 1997:14:144-157. 31. Pontes Andersen CC, Flyvbjerg A, Buschard K, Holmstrup P. Periodontitis is associated with aggravation of prediabetes in Zucker fatty rats. J Periodontol 2007;78:559-565. 32. Sun QY, Feng M, Zhang MZ et al. Effects of periodontal treatment on glycemic control in type 2 diabetic patients: a meta-analysis of randomized controlled trials. Chin J Physiol 2014;57:305-314. 33. Taheri JB, Azimi S, Rafieian N, Zanjani HA. Herbs in dentistry. Int Dent J 2011;61:287-296. 34. Choonhakarn C, Busaracome P, Sripanidkulchai B, Sarakarn P. The efficacy of aloe vera gel in the treatment of oral lichen planus: a randomized controlled trial. Br J Dermatol 2008;158:573-577. 35. López-Jornet P, Camacho-Alonso F, Molino-Pagan D. Prospective, randomized, double-blind, clinical evaluation of Aloe vera Barbadensis, applied in combination with a tongue protector to treat burning mouth syndrome. J Oral Pathol Med 2013;42:295-301. 36. Pradeep AR, Agarwal E, Naik SB. Clinical and microbiologic effects of commercially available dentifrice containing aloe vera: a randomized controlled clinical trial. J Periodontol 2012;83:797-804. 37. Abdelmonem HM, Khashaba OH, Al-Daker MA, Moustafa MD. Effects of aloe vera gel as an adjunctive therapy in the treatment of chronic periodontitis: a clinical and microbiologic study. Mansoura J Dent 2014;1:11-19. 38. Fani M, Kohanteb J. Inhibitory activity of aloe vera gel on some clinically isolated cariogenic and periodontopathic bacteria. J Oral Sci 2012;54:15-21. 39. Pradeep AR, Agarwal E, Naik SB. Clinical and microbiologic effects of commercially available dentifrice containing aloe vera: a randomized controlled clinical trial. J Periodontol 2012;83:797-804.
CORRESPONDING AUTHOR: Dr. A. R. Pradeep MDS, Professor, Head and PhD Guide, Department of Periodontics, Government Dental College and Research Institute, Bangalore560002, Karnataka, INDIA, Email: [email protected] (e-mail to be published), Fax: 080-26703176 Submitted March 11, 2015; accepted for publication September 12, 2015. Figure 1: CONSORT FLOW CHART Table 1: Basic demographic characteristics of the study PARAMETER GROUP 1 GROUP 2 30 30 No. of patients (n) 34.76 ± 5.57 35.03 ± 4.78 Mean age ± SD (yrs) 25-45 27-44 Age (yrs) 16/14 17/13 Male / female
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Table 2: Clinical Parameters for Groups 1 and 2 (mean ± SD) at Different Time Intervals Parameter Visit GROUP 1 GROUP 2 F-Value 2.77 ± 0.43 2.73 ± 0.45 0.086 PI BL 2.10 ± 0.71 1.67 ± 0.48 7.646 3m 1.43 ± 0.62 1.33 ± 0.60 0.395 6m 2.9 ± 0.40 2.93 ± 0.25 0.147 mSBI Baseline 2.23 ± 0.67 1.70 ± 0.53 11.422 3 months 1.73 ± 0.58 1.57 ± 0.5 1.402 6 months 7.27 ± 0.92 7.26 ± 0.94 0.076 PD (mm) Baseline 6.10 ± 0.99 5.43 ± 0.97 6.897 3 months 5.27 ± 0.98 4.60 ± 0.93 7.286 6 months 6.17 ± 0.91 6.23 ± 0.89 0.081 CA level Baseline (mm) 5.37 ± 0.99 5.17 ± 0.87 0.681 3 months 5.10 ± 0.92 4.57 ± 0.89 5.148 6 months
p-Value 0.770 0.008* 0.532 0.703 0.001* 0.241 0.783 0.011* 0.009* 0.776 0.413 0.027*
(*denotes statistically significant difference, p < 0.05) Table 3: Comparison of Mean Change from Baseline between the Visits in groups 1 and 2 Parameter Group BL - 3months p-Value BL – 6 months p-Value PI mSBI PD (mm) CAL (mm)
1 2 1 2 1 2 1 2
0.67 ± 0.47 1.07 ± 0.25 0.67 ± 0.60 1.23 ± 0.50 1.10 ± 0.54 1.83 ± 0.37 0.80 ± 0.40 1.07 ± 0.25
DOI: 10.1902/jop.2015.150161
Adjunctive Local Delivery of Aloe Vera Gel in Type 2 Diabetics With Chronic Periodontitis : A Randomized Controlled Clinical Trial Dr. A R Pradeep MDS*, Dr. Vibhuti Garg BDS (MDS)*, Dr. Arjun Raju MBBS (MD)†, Dr. Priyanka Singh MBBS (MS)‡ *Department of Periodontology, Government Dental College and Research Institute, Bengaluru-560002, Karnataka, India. †
‡
Department of Radio-diagnosis, Uttarakhand Government Medical College, Haldwani (Nainital – 263129), Uttarakhand, India.
Department of Ophthalmology, Grant Medical College & JJ Group of Hospitals, JJ Marg, Nagpada-Mumbai Central, Off Jijabhoy Road, Mumbai-400008, Maharashtra, India.
BACKGROUND: Herbal agents, like Aloe vera (AV), have been in use for both medical and dental therapy since historical times. AV has anti-inflammatory, antioxidant, antimicrobial, hypoglycaemic, healing promoting and immune boosting properties. This study is aims at investigating the clinical effectiveness of locally delivered AV gel used as an adjunct to scaling and root planing (SRP) in the treatment of type 2 DM patients with chronic periodontitis (CP). MATERIAL AND METHODS: Sixty patients with probing depth (PD) ≥5mm and clinical attachment (CA) level ≥3mm were randomly divided into two groups. All patients underwent SRP. Placebo gel was locally delivered in Group 1 patients and AV gel in Group 2 patients. Clinical recording of full mouth plaque index (PI), modified sulcus bleeding index (mSBI), probing depth (PD) and clinical attachment (CA) level was done first at baseline and then at intervals of 3 months and 6 months. RESULT: Patients in AV group showed significantly greater mean reductions in PI, mSBI and PD and mean gain in CA level compared to those in placebo group from baseline to 3 months. Gain in CA level was significantly greater in AV group at all time intervals than the placebo group. CONCLUSION: Adjunctive use of AV gel LDD, in comparison to placebo gel LDD, is associated with greater reduction in PI, mSBI and PD as well as more gain in CA level in type 2 diabetics with CP.
KEY WORDS: Chronic periodontitis; dental scaling; regeneration; aloe.
Chronic periodontitis (CP) is inflammation of periodontium induced by microbes leading to gingival inflammation, periodontal tissue destruction and alveolar bone loss.1 Host response to infection, rather than the infectious agent itself, is the cause of most of the tissue damage in periodontal disease.2 This involves innate immune response activation with upregulation of monocytes/polymorphonuclear leukocyte-derived proinflammatory cytokines and downregulation of macrophage-derived growth factors.3 Symbiosis between diabetes and periodontitis is evident in the poor glycaemic control seen in CP patients and increased prevalence and severity of periodontitis seen in diabetic patients.4 Periodontitis has indeed been identified as the sixth complication of diabetes mellitus (DM).5 Periodontal therapy encompasses a broad range of treatment modalities, including nonsurgical periodontal therapy (NSPT), such as scaling and root planing (SRP) alone or with adjunctive administration of systemic or local antimicrobial/anti-inflammatory agents and surgical (resective and/or regenerative) periodontal therapy.6 Traditionally, dental practitioners have depended on mechanical debridement (SRP) in managing periodontal infections.7 However, it is associated with a high rate of recurrence of
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periodontal disease7 and may fail to reduce or eliminate the anaerobic infection at the base of the pocket, inaccessible areas like the furcation, within the gingival tissues and structures inaccessible to periodontal instrumentation like in sites with probing depths exceeding 5mm.8 An effective adjunct would be local drug delivery (LDD) systems, which provide controlled release of the therapeutic agent at specific subgingival sites, thus translating into high concentrations at the target site with reduced dosage, fewer side effects compared to systemic drugs, fewer applications and high patient acceptance.9,10 Systemic administration, though found to be effective in treating periodontal pockets, requires prolonged repeated administration of a relatively high dose to achieve the required sulcular concentrations, thus raising the chances of pathogens developing resistance and commensal flora being altered with host expressing adverse effects like allergic/ anaphylactic reaction, gastric disturbances, superinfection, nausea, vomiting, etc.11 Since historical times, various herbal and natural products have been used for chemotherapeutic purposes in the field of medicine and dentistry, with the advantage of fewer side effects and cost-effectiveness.12 Aloe vera (AV) is one such medicinal, perennial succulent plant belonging to the Liliaceae Family, with anti-inflammatory,13 antioxidant,14 antibacterial,15 antiviral,16 antifungal17 and immune boosting properties.18 It also promotes wound healing by accelerating epithelial cell migration and collagen maturation, facilitating tissue restoration.19 Acemannan, a polysaccharide from AV, has also been found to have osteogenic properties.20 AV has also shown hypoglycemic and hypolipidemic effects in noninsulin dependent diabetics, causing significant reduction in blood glucose levels, blood pressure and lipid profile of the diabetic patients.21 In view of these properties, local delivery of AV may be evaluated for its usefulness in the treatment of inflammatory diseases like CP,1 especially those aggravated by type 2 DM.4 The novel use of this herbal product may serve to widen the treatment options for CP deteriorated by DM. Till date, we have not come across any study evaluating the clinical effects of locally delivered (LD) AV gel in type 2 diabetics with CP. Hence, the present study was designed to evaluate the clinical affects of LD AV gel and compare it with LD placebo gel as an adjunct to SRP in type 2 diabetics with CP.
MATERIALS AND METHODS Source of Data This was a single-centre, randomized, longitudinal, triple masked, interventional study, the patients for which were selected from the outpatient section of the Department of Periodontology, Government Dental College and Research Institute (GDCRI), Bengaluru. Sixty patients (33 males and 27 females), aged 25 to 45 years (mean ± SD = 34.76 ± 5.15 years) with a diagnosis of CP and type 2 DM, voluntarily enrolled in this study, after providing a written informed consent. The Ethical Committee, GDCRI, Bengaluru provided the ethical clearance for the study. The period of study was from June 2014 to December 2014 (ClinicalTrials.gov Identifier: NCT02386020). Selection Criteria Patients with well-controlled type 2 DM (selected according to American Diabetes Association criteria 2013)22 and CP with moderate to deep pockets [probing depth (PD) ≥5mm23 and clinical attachment (CA) loss ≥3mm24] without any history of periodontal or antibiotic therapy in past 6 months were included. Exclusion criteria were: presence of any other known disease/condition or intake any medication that can affect the periodontal status,
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allergy (known or suspected) to herbal medications, systemic antimicrobial therapy, aggressive periodontitis, smoking, alcoholism, immunocompromised state and pregnant or lactating females. Patients were selected based on these criteria (by VG) and coin toss was used to randomly allocate 30 patients to each treatment group. One site per patient, i.e. the site with the maximum PD and CA loss and with bleeding on probing (BOP), received SRP at baseline until the root surfaces appeared clean and smooth, followed by LDD of placebo gel (in group 1) or AV in situ gel (in group 2) (by VG). No medications (such as antibiotics, anti-inflammatory or antiplaque agents) were prescribed after treatment. Clinical parameters, including modified sulcus bleeding index (mSBI),25 full-mouth and site-specific plaque index (PI),26 PD and clinical attachment (CA) level, were recorded at baseline (before SRP) and at 3 and 6 months after LDD. A custom-made acrylic stent and a University of North Carolina (UNC) no.15 color-coded periodontal probe§ were used to standardize the measurement of PD and CA level. CA loss was calculated by measuring the distance from the stent (apical extent) to the base of the pocket minus the distance from the stent to the cemento-enamel junction (CEJ). Treatment to both the groups was provided by a single clinician (VG) and all the pre- and post-treatment clinical measurements were recorded by another examiner (ARP), who was masked to the type of treatment received by the patients. The adjusted mean at each visit is shown in Tables 2. Intra-Examiner Calibration Before beginning the study, 20 patients were examined twice, 24 hours apart. If the difference between the measurements made at baseline and after 24 hours was within 1 mm at the 95% level, intra-examiner calibration was accepted. Formulation of AV in Situ Gel After intensive in vitro investigations for optimization and stability, the AV gel was developed at the Government College of Pharmacy, Bengaluru, following the procedure described by Velam et al.27 The central parenchymatous pulp from aloe leaves was washed repeatedly with water and finally with 0.1N sodium hydroxide (NaOH). The treated pulp was placed in a blender to obtain the juice. This juice was prefiltered using a cotton bed and then patiented to repeated vacuum filtration until a clear liquid was obtained. To this, 1% w/w carbopol 934 and 0.5% w/w methyl paraben were added and dispersed uniformly. Carbopol gellifies under alkaline conditions. A 0.5N NaOH solution was added dropwise using moderate agitation until a gel was formed. The prepared AV gel was weighed and stored in air tight containers in a dark room to prevent photooxidation.27 Both, AV gel and placebo gel were prepared similar in color and consistency so as not to affect the examiners blinding. Local Drug Delivery For standardization, a blunt cannula was used to deliver 0.1 ml of the prepared placebo or gel into the periodontal pockets at the control/test site, respectively. After delivery, the viscosity of the prepared formulation decreased, swelling up and occluding the periodontal pocket, precluding the need for placement of periodontal dressing. After in situ gel placement, patients were instructed to avoid brushing or using any interdental aids near the treated areas or chewing hard or sticky foods, for 1 week. At the recall visits, supragingival deposits, if any, were removed and adverse effects, if any, were noted.
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Statistical Analysis: The data were analyzed using a SPSS statistical software program.ǁ Before initiating the study, sample size was determined by power calculations. The primary outcome measure was the difference between the groups in mean CA level change from baseline to the end of follow-up. To achieve a 90% statistical power, an unpaired t-test suggested inclusion of minimum 25 patients in each group (assuming an α-error=0.05 and an expected withdrawal/dropout rate of 15%). The results were averaged for each clinical parameter at baseline, 3 and 6 months. Shapiro-Wilk's W test was employed to test the normality assumption of the data. The mean changes in the parameters were calculated from baseline to 3 and 6 months. For all clinical parameters, the significance of inter-group differences were assessed using analysis of variance (ANOVA) test. Repeated measure ANOVA was used to evaluate the statistical significance of mean change from baseline to follow-up visits within the groups. A t-test was employed to determine the significance of differences between the groups and p values 0.05) (Table 2). Within each group, the mean changes for all the parameters were significant at all intervals (Table 3). Inter-group comparison (Table 4) shows that there was a significantly greater mean reduction in all parameters from baseline to 3 months in the AV group than the placebo group. AV group also showed significantly greater mean reduction in PI and mSBI in the 3-6 months interval as well as in PD from baseline to 6 months. Mean gain in CA level was significantly greater in the AV group at all time intervals than the placebo group.
DISCUSSION Periodontitis and DM have a bidirectional relationship.28 Periodontal infection is associated with transient bacteremias due to breach in periodontal attachment integrity.29 These bacteria and their toxins pose a systemic challenge, linking periodontitis to hyperinflammatory response state and metabolic dysregulation in diabetes.29 Accumulation of advanced glycation end products (AGEs) in diabetes induces an exaggerated monocytic inflammatory response, resulting in exaggerated secretion of local and systemic inflammatory mediators mediating periodontal tissue destruction.29 The severity and incidence of progressive periodontal disease is increased two to three fold in diabetics,28 in association with impaired collagen generation and exaggerated collagenase activity.30 Moreover, blood glucose levels have been found to be higher in periodontitis patients and in diabetic rats with experimental periodontitis.31 Thus, improvement in metabolic control can be achieved by effective periodontal therapy in of type 2 diabetes. A meta-analysis by Sun et al32 revealed that periodontal treatment could decrease HbA1c levels and improve glycemic status in type 2 diabetics with periodontal diseases.
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Conventional non-surgical periodontal therapy is based on the elimination of foci of infections by mechanical debridement, including SRP, as well as local drug delivery (LDD) of therapeutic agents, such as herbal products, into periodontal pockets. Use of medicinal herbs or their extracts are effective in preventing and treating oral conditions.33 Aloe vera is one such herbal plant, used in dentistry for the treatment of oral lichen planus,34 burning mouth syndrome,35 gingivitis36 and periodontal diseases.37 The current study clinically evaluated the adjunctive use of AV gel with SRP for the treatment of type 2 diabetics with CP and found the improvement in clinical parameters to be significantly more with AV compared to placebo gel. Significant reduction in full mouth PI can be explained by antibacterial effect of AV on periodontal bacteria.15,38 There was also a significant reduction in mSBI, which can be attributed to the anti-inflammatory13 and antibacterial38 properties of AV. AV also accelerates collagen synthesis and promotes wound healing,19 that can account for the significant PD reduction and significant CA level gain. Gain in CA level was significantly higher with AV LDD at all time intervals, suggesting regenerative potential of this herbal agent. The mean reduction in PI and mSBI and the mean CA level gain was significantly greater in AV group in the 3-6 months interval, suggesting long term benefits of this local delivery system. These findings are in accordance with those of Abdelmonem et al,37 who found AV LDD as an adjunct to mechanical periodontal therapy to be associated with significant improvement in microbiologic as well as clinical outcomes in CP patients. In our previous study, we found that toothpaste containing AV was effective in reducing the microbial colonies of S. sangius, S. oralis, Actinomyces viscosus and Actinomyces naeslundii in patients with chronic gingivitis.39 Hence, local delivery of AV may be associated with even greater reduction of these periopathogens. The above-mentioned properties, along with the ease of availability, no known adverse effects and cost effectiveness make AV an ideal candidate for treatment of immune-inflammatory conditions like CP in type 2 diabetics. Considering these facts, direct subgingival delivery of AV as an adjunct to SRP can be proposed as a better approach for treatment of periodontal pockets in type 2 diabetics with CP compared to SRP with or without placebo gel LDD. Further, multi-center, long term, double blinded, randomized clinical trials with glycaemic status assessment, histological bone gain evaluation and microbiologic profile determination are needed to confirm the findings in this study.
CONCLUSION: It can thus be demonstrated from this clinical trial that AV gel, delivered locally into periodontal pockets, as an adjunct to SRP, in type 2 diabetics with CP, stimulated a significant improvement in clinical parameters as compared to placebo gel. Thus, use of complementary and alternative medicine can provide new therapeutic options in patients who are at greater risk for periodontal destruction. ACKNOWLEDGEMENTS: We would like to express our gratitude to Sneha Pharmaceuticals, Bengaluru, India for providing us samples of AV as well as to Prof. B.G Shivananda, Principal, Government College of Pharmacy, Bangalore, India for his help in the preparation the LDD gels.
DISCLOSURE: The authors declare that they have no conflict of interests. Authors declare no financial support or relationships that may pose conflict of interest.
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CORRESPONDING AUTHOR: Dr. A. R. Pradeep MDS, Professor, Head and PhD Guide, Department of Periodontics, Government Dental College and Research Institute, Bangalore560002, Karnataka, INDIA, Email: [email protected] (e-mail to be published), Fax: 080-26703176 Submitted March 11, 2015; accepted for publication September 12, 2015. Figure 1: CONSORT FLOW CHART Table 1: Basic demographic characteristics of the study PARAMETER GROUP 1 GROUP 2 30 30 No. of patients (n) 34.76 ± 5.57 35.03 ± 4.78 Mean age ± SD (yrs) 25-45 27-44 Age (yrs) 16/14 17/13 Male / female
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Table 2: Clinical Parameters for Groups 1 and 2 (mean ± SD) at Different Time Intervals Parameter Visit GROUP 1 GROUP 2 F-Value 2.77 ± 0.43 2.73 ± 0.45 0.086 PI BL 2.10 ± 0.71 1.67 ± 0.48 7.646 3m 1.43 ± 0.62 1.33 ± 0.60 0.395 6m 2.9 ± 0.40 2.93 ± 0.25 0.147 mSBI Baseline 2.23 ± 0.67 1.70 ± 0.53 11.422 3 months 1.73 ± 0.58 1.57 ± 0.5 1.402 6 months 7.27 ± 0.92 7.26 ± 0.94 0.076 PD (mm) Baseline 6.10 ± 0.99 5.43 ± 0.97 6.897 3 months 5.27 ± 0.98 4.60 ± 0.93 7.286 6 months 6.17 ± 0.91 6.23 ± 0.89 0.081 CA level Baseline (mm) 5.37 ± 0.99 5.17 ± 0.87 0.681 3 months 5.10 ± 0.92 4.57 ± 0.89 5.148 6 months
p-Value 0.770 0.008* 0.532 0.703 0.001* 0.241 0.783 0.011* 0.009* 0.776 0.413 0.027*
(*denotes statistically significant difference, p < 0.05) Table 3: Comparison of Mean Change from Baseline between the Visits in groups 1 and 2 Parameter Group BL - 3months p-Value BL – 6 months p-Value PI mSBI PD (mm) CAL (mm)
1 2 1 2 1 2 1 2
0.67 ± 0.47 1.07 ± 0.25 0.67 ± 0.60 1.23 ± 0.50 1.10 ± 0.54 1.83 ± 0.37 0.80 ± 0.40 1.07 ± 0.25
