Clinical Effect of Subgingivally Delivered Simvastatin in the Treatment of Patients With Chronic Periodontitis: A Randomized Clinical Trial Avani R. Pradeep* and Manojkumar S. Thorat* Background: Periodontitis is an inflammatory disease that re- sults in bone resorption creating bony defects, which may cause tooth loss. Various drugs have been studied using local delivery to improve the periodontal health and to achieve periodontal regener- ation. Simvastatin (SMV) is a specific competitive inhibitor of 3-hy- droxy-2-methyl-glutaryl coenzyme A reductase. The present study was designed to investigate the effectiveness of SMV, 1.2 mg, in an indigenously prepared biodegradable controlled-release gel as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis. Methods: Sixty patients were categorized into two treatment groups: SRP plus placebo (group 1) and SRP plus SMV, 1.2 mg (group 2). Clinical parameters were recorded at baseline before SRP and at 1, 2, 4, and 6 months; they included modified sulcus bleeding index (mSBI), probing depth (PD), and clinical attachment level (CAL). At baseline and after 6 months, radiologic assessment of intrabony defect (IBD) fill was done using computer-aided software. The mean concentration of SMV in gingival crevicular fluid was esti- mated by reverse-phase high-performance liquid chromatography. Results: All subjects tolerated the drug, without any postapplica- tion inflammation. Both therapies resulted in significant improve- ments. The decrease in mSBI score at 6 months was greater in group 2 (2.3267 – 0.8017) compared to group 1 (0.5033 – 0.6815). The mean decrease in PD from baseline to 6 months was 1.20 – 1.24 mm and 4.26 – 1.59 mm in groups 1 and 2, re- spectively. Mean CAL gain from baseline to 6 months was 1.63 – 1.99 mm and 4.36 – 1.92 mm in groups 1 and 2, respectively. In group 2, there was greater decrease in mean IBD (1.41 – 0.74 mm or 32.54%) compared to group 1 (0.09 – 0.58 mm or 2.16%). Conclusion: There was a greater decrease in gingival index and PD and more CAL gain with significant IBD fill at sites treated with SRP plus locally delivered SMV in patients with chronic periodontitis. J Periodontol 2010;81:214-222. KEY WORDS Chromatography, high pressure liquid; chronic periodontitis; drug delivery systems; periodontal regeneration; root planing; simvastatin. C hronic inflammatory peri- odontal disease 1 is highly prevalent, especially in late middle age, when cardiovascu- lar disease is also common. In periodontitis, the production of proinflammatory cytokines and tissue-degradative enzymes is ini- tiated and advanced by oral bac- terial infection, ultimately resulting in the destruction of periodontal tissue. Periodontitis, as an inflam- matory disease occurring adjacent to bone, leads to bone resorption, creating bony defects that may cause tooth loss. Various methods are effective in repairing these de- fects, creating space, and stimu- lating host bone formation through the use of a graft, guided tissue regeneration, and growth factors. 2 Many treatment modalities are available to achieve the goal of peri- odontal therapy. This includes non- surgical periodontal therapy, such as scaling and root planing (SRP) alone or SRP plus systemic or lo- cal antimicrobial/anti-inflammatory agents, and surgical periodontal therapy. Autologous bone is the current gold-standard graft material for the treatment of skeletal defects and fracture repair. 3 However, the need for a second surgical site and the limited supply of bone available * Department of Periodontics, Government Dental College and Research Institute, Karnataka, India. doi: 10.1902/jop.2009.090429 Volume 81 • Number 2 214
Transcript
Clinical Effect of Subgingivally DeliveredSimvastatin in the Treatmentof Patients With Chronic Periodontitis:A Randomized Clinical TrialAvani R. Pradeep* and Manojkumar S. Thorat*
Background: Periodontitis is an inflammatory disease that re-sults in bone resorption creating bony defects, which may causetooth loss. Various drugs have been studied using local delivery toimprove the periodontal health and to achieve periodontal regener-ation. Simvastatin (SMV) is a specific competitive inhibitor of 3-hy-droxy-2-methyl-glutaryl coenzyme A reductase. The present studywas designed to investigate the effectiveness of SMV, 1.2 mg, in anindigenously prepared biodegradable controlled-release gel as anadjunct to scaling and root planing (SRP) in the treatment of chronicperiodontitis.
Methods: Sixty patients were categorized into two treatmentgroups: SRP plus placebo (group 1) and SRP plus SMV, 1.2 mg(group 2). Clinical parameters were recorded at baseline beforeSRP and at 1, 2, 4, and 6 months; they included modified sulcusbleeding index (mSBI), probing depth (PD), and clinical attachmentlevel (CAL). At baseline and after 6 months, radiologic assessment ofintrabony defect (IBD) fill was done using computer-aided software.The mean concentration of SMV in gingival crevicular fluid was esti-mated by reverse-phase high-performance liquid chromatography.
Results: All subjects tolerated the drug, without any postapplica-tion inflammation. Both therapies resulted in significant improve-ments. The decrease in mSBI score at 6 months was greater ingroup 2 (2.3267 – 0.8017) compared to group 1 (0.5033 –0.6815). The mean decrease in PD from baseline to 6 monthswas 1.20 – 1.24 mm and 4.26 – 1.59 mm in groups 1 and 2, re-spectively. Mean CAL gain from baseline to 6 months was 1.63 –1.99 mm and 4.36 – 1.92 mm in groups 1 and 2, respectively. Ingroup 2, there was greater decrease in mean IBD (1.41 – 0.74 mmor 32.54%) compared to group 1 (0.09 – 0.58 mm or 2.16%).
Conclusion: There was a greater decrease in gingival index andPD and more CAL gain with significant IBD fill at sites treated withSRP plus locally delivered SMV in patients with chronic periodontitis.J Periodontol 2010;81:214-222.
Chronic inflammatory peri-odontal disease1 is highlyprevalent, especially in late
middle age, when cardiovascu-lar disease is also common. Inperiodontitis, the production ofproinflammatory cytokines andtissue-degradative enzymes is ini-tiated and advanced by oral bac-terial infection, ultimately resultingin the destruction of periodontaltissue. Periodontitis, as an inflam-matory disease occurring adjacentto bone, leads to bone resorption,creating bony defects that maycause tooth loss. Various methodsare effective in repairing these de-fects, creating space, and stimu-lating host bone formation throughthe use of a graft, guided tissueregeneration, and growth factors.2
Many treatment modalities areavailable to achieve the goal of peri-odontal therapy. This includes non-surgical periodontal therapy, suchas scaling and root planing (SRP)alone or SRP plus systemic or lo-cal antimicrobial/anti-inflammatoryagents, and surgical periodontaltherapy. Autologous bone is thecurrent gold-standard graft materialfor the treatment of skeletal defectsand fracture repair.3 However, theneed for a second surgical site andthe limited supply of bone available
* Department of Periodontics, Government Dental College and Research Institute, Karnataka, India.
doi: 10.1902/jop.2009.090429
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have led to the development of various alternativematerials. Protein growth factors (like bone morpho-genetic proteins) are expensive, may degrade rapidlyat the treatment site, and could potentially elicit im-mune responses, thus limiting their use.4 If pharma-cologic compounds can upregulate the necessaryautogenous growth factors to stimulate bone growth,this approach may prove to be a cost-effective way tocorrect bone defects.
Statins like simvastatin (SMV), lovastatin, andpravastatin are specific competitive inhibitors of3-hydroxy-2-methyl-glutaryl coenzyme A (HMG-CoA) reductase.5-7 These agents are widely used tolower cholesterol, and they provide an importantand effective approach for the treatment of hyperlip-idemia and arteriosclerosis.8 Statins also seem tomodulate bone formation by increasing the expres-sion of bone morphogenetic protein-2, inflammation,and angiogenesis,9 thus providing a new direction inthe field of periodontal therapy. Various animal stud-ies10-12 showed that SMV assists in bone regenerationas well as the anti-inflammatory effect when deliv-ered or applied locally. Sakoda et al.11 measuredthe effect of SMV on interleukin (IL)-6 and -8 produc-tion in a cultured human epithelial cell line (KB cells)in response to IL-1. SMV decreased the production ofIL-6 and -8, an effect that was reversed by addingmevalonate or geranylgeranyl pyrophosphate butnot farnesyl pyrophosphate. SMV reduced nuclearfactor-kappa B and activator protein 1 promoteractivity in KB cells, indicating an anti-inflammatoryeffect for SMV on human oral epithelial cells, appar-ently involving Rac1 GTPase (a hydrolase enzymethat can bind and hydrolyze guanosine triphosphate)inhibition.
Various vehicles, such as lactide/glycolide poly-mer,13,14 hydroxypropyl methylcellulose,15 and car-bopol,16,17 have been mentioned and used in theliterature for controlled-drug release. Local drug-delivery systems, such as tetracycline releasing ethyl-ene vinyl acetate monolithic fiber,18 2% minocyclineointment,19 25% metronidazole gel,20 chlorhexidinewith ethyl cellulose film,21 and chlorhexidine, 2.5 mg,in chip form,22 have been used for local drug deliveryin patients with periodontitis. Vehicles used are bio-compatible, have predictable biodegradation kineticsand ease of fabrication, and have regulatory approval;thus, they have wide applications in controlled drug-delivery systems.23 Methylcellulose is widely usedin a variety of oral and topical pharmaceutical formu-lations, such as ophthalmic controlled-release insitu gelling systems for ciprofloxacin and nimesu-lide-loaded methylcellulose nanoparticles and micro-particles for oral delivery.24,25 It is used extensivelyin cosmetic and food products. Methylcellulose isgenerally regarded as a non-toxic, non-allergic, and
non-irritating material and is used as a sustained-released vehicle for therapeutic drugs.26
To the best of our knowledge, there are no pub-lished data on the use of in situ gel using SMV withmethylcellulose (as a vehicle) for direct placementin the periodontal pocket of patients with chronic peri-odontitis. Keeping the above facts in mind, the presentstudy was carried out as a single-center, randomizedcontrolled clinical trial to investigate the clinicaland radiologic (bone fill) efficacy of SMV, 1.2 mg,as an adjunct to SRP in the treatment of chronic peri-odontitis.
MATERIALS AND METHODS
Source of DataThe patients for this study were selected from the out-patient section of the Department of Periodontics,Government Dental College and Research Institute,from December 2008 to May 2009. Sixty-four pa-tients, aged 25 to 45 years (33 males and 31 females,mean – SD = 30.5 – 4.1 years) and who were diag-nosed with chronic periodontitis, were enrolled in thisstudy. It was made clear to the potential subjects thatparticipation was voluntary. Written informed consentwas obtained from patients, and ethical clearance forthe study was received from the Ethical Committee,Government Dental College and Research Institute.
Selection CriteriaSystemically healthy patients with moderate (probingdepth [PD] of 5 to 6 mm or clinical attachment loss[CAL] of 4 to 6 mm; n = 24) or deep pockets (PD ‡7mm or CAL of 6 to 9 mm; n = 36) and vertical boneloss ‡3 mm on intraoral periapical radiographs andno history of antibiotic or periodontal therapy in thepreceding 6 months were included. Patients withknown or suspected allergy to the SMV group, thoseon systemic statin therapy, patients with aggressiveperiodontitis, smokers, alcoholics, patients with dia-betes, immunocompromised patients, and pregnantor lactating females were excluded.
After subject selection (by MST), 30 patients wererandomly (by coin toss) assigned to each treatmentgroup, and one site per subject was treated withSRP plus placebo gel (group 1) or SRP plus SMV(1.2 mg/0.1 ml) in situ gel (group 2). SRP wasperformed at baseline until the root surface was con-sidered smooth and clean by the operator (MST).No antibiotics or antiplaque and anti-inflammatoryagents were prescribed after treatment.
Clinical parameters, including modified sulcusbleeding index (mSBI)27 and full-mouth and site-spe-cific plaque score (PI),28 were considered, and PD andCAL were recorded at baseline (before the SRP) and at1, 2, 4, and 6 months. A custom-made acrylic stentand a University of North Carolina no. 15 color-coded
J Periodontol • February 2010 Pradeep, Thorat
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periodontal probe† were used to standardize the mea-surement of PD and CAL. CAL was calculated by mea-suring the distance from the stent (apical extent) tothe base of the pocket minus the distance from thestent to the cemento-enamel junction.
A single clinician (MST) provided treatment to bothgroups, and all pre- and post-treatment clinical pa-rameters were recorded by another examiner PRAwho was masked to the type of treatment receivedby the subjects.
Radiographic Evaluation of IntrabonyDefects (IBDs)Bone fill was evaluated at baseline and after 6 monthsusing an image analyzer.‡ The radiographic IBD depthwas measured with a computer-aided program ac-cording to the method used by Francetti et al.29 Indi-vidually customized bite blocks and a parallel-angletechnique were used to obtain films as reproducibleas possible. All radiographs were reviewed in a singlereference center by a masked evaluator. For eval-uation, radiographs were scanned at 800 dots perinch with a scanner,§ and IBD was evaluated usingcomputer-aided software. IBD was measured on theradiograph by measuring the vertical distance fromthe crest of the alveolar bone to the base of the defect(Figs. 1 and 2).
Formulation of 1.2% SMV In Situ GelAfter intensive in vitro investigations for optimizationand stability, the SMV gel was developed at the Gov-ernment College of Pharmacy, Bangalore.
Methylcellulose in situ gel was prepared as de-scribed by Thylin et al.30 Briefly, methylcellulose insitu gel was prepared by adding the required amount
of biocompatible solvent to an accurately weighedamount of methylcellulose. The vial was heated to50�C to 60�C and agitated using a mechanical shakerto obtain a clear solution. A weighed amount of SMVwas added to the above solution and dissolved com-pletely to obtain a homogeneous phase of polymer,solvent, and drug. Thus, the SMV in situ gel was pre-pared with a concentration ;1.2%.
Local Drug DeliveryFor standardization, 0.1 ml prepared SMV gel(1.2 mg/0.1 ml) was injected into the periodontalpockets using a syringe with a blunt cannula. No peri-odontal dressing was applied after delivery of the drugbecause the prepared formulation decreases in vis-cosity, which causes swelling and occlusion of theperiodontal pocket.
After placement of the in situ gel, patients were in-structed to refrain from chewing hard or sticky foods,brushing near the treated areas, or using any inter-dental aids for 1 week. Adverse effects were notedat recall visits, and any supragingival deposits wereremoved.
Collection of Gingival Crevicular Fluid(GCF) SamplesGCF was collected from drug-delivery sites in six ran-domly selected patients from group 2 (SRP + SMV) us-ing 1- to 5-ml calibrated volumetric microcapillarypipettesi at baseline; at 2, 4, 6, and 24 hours; and
Figure 1.IBD was measured on the baseline radiograph, by measuring the verticaldistance from the crest of the alveolar bone to the base of the defect(5.23 mm).
Figure 2.IBD was measured on the radiograph of the same area after 6 months, bymeasuring a vertical distance from the crest of the alveolar bone to thebase of the defect (2.34 mm).
† Hu-Friedy, Chicago, IL.‡ Scion Image Analyzer, Scion, Frederick, MD.§ HP Scanjet 3c/I, Hewlett Packard, Singapore.i Sigma-Aldrich, St. Louis, MO.
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on days 2, 7, 14, 21, and 30. Collected samples werestored at 4�C to 8�C until the estimation was done.
Estimation of Quantity of SMVThe drug estimation was done using gradient reverse-phase high-performance liquid chromatography¶
(HPLC) with pumps, a variable wavelength program-mable ultraviolet/visible spectroscopy detector, anda system controller; an operating software data sta-tion# was used.
Chromatographic ConditionsA column** (150 mm [length] · 4.6 mm [internal di-ameter] and particle size of 5 mm) was used as thestationary phase. The mobile phase consisted of35% volume of buffer (0.1% phosphoric acid) and65% volume of acetonitrile (volume/volume). Themobile phase was filtered through a 0.45-mm-mem-brane filter†† and sonicated to remove air bubbles.The flow rate was 1.0 ml/minute, and the column ef-fluent was monitored at 238 nm.
Calibration Curve in GCFA standard stock solution of SMV (1 mg/ml) was pre-pared in acetonitrile in a 100 ml volumetric flask, add-ing 30 to 40 ml diluent prepared by mixing 40%volume of 1.4 g/l solution of dihydrogen phosphate,pH 4, with phosphoric acid and 60% volume of aceto-nitrile. The flask was sonicated to dissolve the sol-vents. The standard stock solutions were diluted100 times to get a concentration of 10.4 mg/ml byusing the GCF stock solution. GCF stock solutionwas prepared by spiking the GCF samples from 10capillary tubes, obtained at baseline from patients ingroups 1 and 2 for standardization, to the 1 ml solutionthat contained acetonitrile. An aliquot of 80 ml work-ing stock solution (10.4 mg/ml) was added to 20 ml 1%phosphoric acid buffer (in the pH range of 4) in micro-
centrifuge tubes and vortexed for 1 minute. Acetoni-trile was used as an extracting solvent, and 1 ml wastaken for the extraction of SMV. The microcentri-fuge tubes were vortexed for 2 minutes and thencentrifuged at 10,000 revolutions per minute (rpm)in a cold centrifuge for 10 minutes. After centrifuga-tion, an aliquot of 20 ml supernatant solution was in-jected via HPLC. The amount of SMV present ina capillary tube was determined by comparing thepeak responses of the standard and the sample ofSMV solution.
Sample PreparationGCF was transferred to a 1- to 5-ml centrifuge tubecontaining 80 ml acetonitrile. Eighty microliters ofGCF (after transfer) and 20 ml buffer (1% phosphoricacid) were combined in a microcentrifuge tube andvortexed for 1 minute. One milliliter of acetonitrilewas added to the above mixture, and it was vortexedfor 1 minute. Then the solution was centrifuged at10,000 rpm in a cold centrifuge for 10 minutes. Aftercentrifugation, an aliquot of 20 ml supernatant solu-tion was injected via HPLC, and the chromatogramwas recorded. The amount of SMV present in theGCF was determined by comparing the peak re-sponses of the standard and the sample of SMV solu-tion.
Statistical AnalysisA sample size of 30 (each group) was estimated toachieve 90% power to detect a difference of 1.0 be-tween the null hypothesis and the alternative mean.All data were analyzed using a software program.‡‡
Table 1.
PD, CAL, and mSBI for Groups 1 and 2 (mean – SD [range]) at Different Time Intervals
Group Visits PD (mm) CAL (mm) Gingival Index (mSBI)
1 Baseline 6.87 – 1.61 (5 to 11) 6.20 – 1.65 (4 to 9) 2.92 – 0.75 (1.5 to 4.0)1 month 5.13 – 1.87 (3 to10) 4.73 – 2.75 (0 to 9) 1.62 – 1.07 (0.0 to 3.5)2 months 5.20 – 2.06 (2 to 11) 4.43 – 2.85 (0 to 8) 1.85 – 1.20 (0.0 to 4.0)4 months 5.20 – 2.16 (2 to 11) 4.47 – 2.89 (0 to 8) 2.22 – 1.18 (0.0 to 4.0)6 months 5.67 – 2.14 (3 to 11) 4.57 – 2.98 (0 to 9) 2.42 – 1.15 (0.2 to 4.0)
2 Baseline 7.43 – 1.59 (5 to 10) 6.23 – 1.45 (4 to 9) 3.12 – 0.68 (1.7 to 4.0)1 month 4.40 – 1.79 (2 to 9) 3.50 – 2.46 (0 to 9) 1.16 – 0.99 (0.0 to 3.2)2 months 3.63 – 1.38 (2 to 8) 2.80 – 2.06 (0 to 7) 0.90 – 0.82 (0.0 to 2.5)4 months 3.20 – 1.47 (2 to 8) 2.27 – 1.96 (0 to 7) 0.77 – 0.71 (0.0 to 2.5)6 months 3.17 – 1.58 (2 to 9) 1.87 – 2.13 (0 to 8) 0.79 – 0.69 (0.0 to 2.7)
The data were evaluated on the subject basis. Com-parisons between groups 1 and 2 were carried outat each visit using baseline-adjusted analysis of co-variance. The adjusted mean at each visit is shownin Tables 1 and 2.
Further, analysis of the treatment effects wascarried out based on the difference in means frombaseline values. The significance of differences wasevaluated by the Student t test (two-tailed), and Pvalues <0.05 were considered significant. Decreasesin each period were calculated from baseline.
RESULTS
Sixty of 64 patients completed the study. Four pa-tients were excluded because they did not meet theinclusion criteria or refused to participate becauseof reasons unrelated to the study. Sixty treatment sites
(one site/subject) were evaluated for clinical param-eters at baseline (before SRP) and at 1, 2, 4, and6 months; radiographic parameters were recordedat baseline and at 6 months in 60 treatment sites.
Clinical EvaluationNo adverse reaction was observed in any subjectfrom the test group, and no patient reported anydiscomfort. Healing was uneventful. All subjectstolerated the drug, without any postapplication com-plications.
Evaluation of Oral HygieneNo statistically significant difference was found be-tween group 1 and group 2 at any time for full-mouthplaque score or for PI at the test site (Tables 3 and 4).This indicates that both groups maintained compara-ble levels of oral hygiene throughout the study.
Table 2.
Decrease in PD, Gingival Index (mSBI), and CAL Gain From Baseline (mean – SD)at Different Time Intervals for Groups 1 and 2
* Not statistically significant at 0.05 level of significance.
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mSBIA statistically significant decrease in mSBI scoresfrom baseline was found in both groups. The decreasein mSBI score was greater in group 2 (2.32 – 0.80)compared to group 1 (0.50 – 0.68) at 6 months; itwas significant in both groups at the 5% level of signif-icance (P <0.05) (Tables 1 and 2).
PDThe decrease in PD was statistically significant withinboth groups compared to baseline at all time intervals(Tables 1 and 2). When the groups were compared toeach other, the decrease in PD at each time period wasstatistically significant.
CALThe difference from baseline was statistically signifi-cant in both groups, CAL gain was greater in group 2compared to group 1 at all periods, and the differencereached the level of significance (Tables 1 and 2).
IBD FillThere was a greater decrease in mean IBD in group 2(1.41 – 0.74 mm or 32.54%) compared to group 1(0.09 – 0.58 mm or 2.16%), and it was statisticallysignificant (P <0.001; Table 5).
Analysis of SMV Concentration in GCFSMV in GCF peaked at 2 hours after application(11.43 – 0027 mg/ml; Table 6). The mean concentra-tions on days 7, 14, 21, and 30 indicate that SMV was
retained in this target compartment for a long period,suggesting a controlled release of the drug untilday 30.
DISCUSSION
Advantages of using the subgingival drug-deliverysystem include achieving high intrasulcular drug con-centrations, avoiding its systemic side effects, andbetter patient compliance.31,32 Therefore, this in vivostudy using SMV in situ gel formulation was carried outto assess the benefits of a local drug-delivery systemwith a controlled drug release.
SMV is a competitive inhibitor for HMG-CoA re-ductase and is widely used in the field of medicineto lower cholesterol, as an effective approach in thetreatment of hyperlipidemia and arteriosclerosis.7
Animal studies3,10,12 showed the effect of SMV onbone regeneration when combined with calcium sul-fate as a carrier or used alone. Morris et al.33 studiedthe effect of injectable SMV in three-walled periodon-tal IBDs, Class 2 furcations defects, and edentulous al-veolar ridges in beagle dogs by histomorphometricanalysis; 29% greater ridge thickness was found withSMV, but bone height loss was detected in the inter-proximal intrabony and furcation defects. However,the present study showed effective IBD fill anda greater decrease in PD and CAL gain compared tothe control group. Yazawa et al.34 studied the effectof SMV on human periodontal (PDL) cells in vitro
Table 4.
Full-Mouth Plaque Scores for Groups 1 and 2 (n = 30 for each group)
Full-Mouth
Plaque Score
Baseline 1 Month 2 Months 4 Months 6 Months
Group 2 Group 1 Group 2 Group 1 Group 2 Group 2 Group 2 Group 1 Group 2 Group 1
1.83 1.85 0.93 0.86 0.91 0.78 0.74 0.68 0.63 0.61
0.35 0.35 0.28 0.31 0.26 0.27 0.30 0.28 0.31 0.27
P value* 0.68 0.40 0.10 0.55 0.77
* Not statistically significant at 0.05 level of significance.
Table 5.
Comparison of IBD Values From Baseline to 6 Months
Group Time IBD (mm; mean – SD)
IBD Decrease
(mm; mean – SD) IBD Decrease (%) Paired t Value P Value
and showed that, at a low concentration, SMV exhibitsa positive effect on the proliferation and osteoblasticdifferentiation of human PDL cells, and these effectsmay be caused by inhibition of the mevalonate path-way.
In the present study there was decreased gingivalbleeding index from baseline to 6 months, suggestingan anti-inflammatory effect of SMV. A similar anti-inflammatory effect of SMV was observed by Lindyet al.35 in patients with chronic periodontitis who wereon systemic statin therapy. Patients with periodontitistaking statins had 37% fewer pathologic periodontalpockets than those not taking statin medication.Sakoda et al.11 showed the anti-inflammatory effectof SMV on human oral epithelial cells, apparently in-volving Rac1 GTPase inhibition, and found decreasedIL-6 and -8 production. A significant mean decrease inIBD from baseline (2.16%) to 6 months (32.54%)in group 2 suggests a role for SMV in bone formation.This may be because of increased bone morphoge-netic protein-2 expression during bone regenera-tion,3 anti-inflammatory effects,10 and angiogenesisduring wound healing. The mean concentration ofSMVatallobservedperiods(frombaseline to30days),as estimated by reverse-phase HPLC, provided suffi-cientanti-inflammatoryactivityand fulfilled thecondi-tions for a controlled-release device. Maintenance ofthisconcentrationof thedrug locally fora longduration(6 months) may have been responsible for the addi-tional improvement in PD, CAL, and bone regenera-tion (IBD fill) in group 2 compared to group 1.
A decrease in PD and gain in CAL are the majorclinical outcomes measured to determine the successof any periodontal treatment. A significant decrease in
PD and gain in CAL were found within both groupscompared to baseline at all time intervals. When com-paring the two groups, the decrease in PD and CALgain were statistically significant at each period, evenafter 6 months (P <0.05). With regard to the dose ofSMV used, 1.2 mg/0.1 ml per site was injected inthe present study. Stein et al.10 demonstrated thatby reducing the SMV dose from 2.2 to 0.5 mg, therewas a decrease in the inflammation to a more clini-cally acceptable level without sacrificing bone-growthpotential. A 45% increase in bone area was reportedwith SMV, 0.5 mg, versus the gel control (similar toa 2.2-mg dose), and clinical swelling was significantlyreduced compared to the high SMV dose. Because itwas difficult to achieve proper viscosity with a lowerconcentration, a 1.2% SMV concentration was usedto prepare a flowable gel that could easily pass throughthe syringe. A decrease in the viscosity of gel was alsostudied in vitro when exposed to ;37�C (mouth tem-perature). The use of smaller (25-gauge) needles withlittle extrusion of drug solution and better dispersion ofthe drug at the site of injection made it easier to injectthe SMV gel at the diseased site.
The possible errors in measuring the IBD fill on ra-diographs, such as those due to exposure settings,geometric error (e.g., radiographic techniques), andthe development of films, were minimized. Anotherfactor that may have caused an error was the use ofconventional film rather than digital images. However,Borg et al.36 assessed the marginal bone level aroundimplants placed in dogs and found no difference inaccuracy and precision between digital and conven-tional films.
CONCLUSIONS
There was a greater decrease in gingival index and PDand more CAL gain with significant IBD fill with locallydelivered SMV in patients with chronic periodontitis.These observations may give new direction in the fieldof periodontal regeneration, to achieve the goal of re-generation without any invasive procedures, therebycausing less discomfort to the patients. However,long-term studies, using different vehicles and con-centrations of SMV, should be carried out to affirmthe observations of our study.
ACKNOWLEDGMENTS
The authors express their gratitude to Mr. Vadiraj, Mr.Athappa, and Mr. Avinash, Masters of Pharmacy stu-dents, Government College of Pharmacy, Bangalore,for providing the drug formulation. The authorsexpress their thanks to BIOCON Pharmaceutical,Bangalore, for providing SMV on request. They alsothank Mr. Mahadevayaih and Mr. Karibasappa, Banga-lore Test House, Bangalore, for HPLC analysis of SMV,and Prof. S.R. Bhimasena Rao, Faculty of English and
Table 6.
SMV Concentration (mean – SD) in GCFAfter Treatment
Time Concentration of SMV (mg/ml)
Baseline 0.00 – 0.00
2 hours 11.43 – 0.027
4 hours 9.49 – 0.40
6 hours 6.52 – 0.30
Day 1 6.12 – 0.11
Day 2 4.28 – 0.37
Day 7 2.46 – 0.36
Day 14 1.19 – 0.36
Day 21 0.77 – 0.12
Day 30 0.22 – 0.19
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Psychology, Regional Vocational Training Institute forWomen, Central Government of India, Bangalore, In-dia, for assistance with English-language editing. Theauthors report no conflicts of interest related to thisstudy.
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Correspondence: Dr. Avani R. Pradeep, Department ofPeriodontics, Government Dental College and Research In-stitute, Fort Bangalore-560002, Karnataka, India. E-mail:[email protected].
Submitted July 23, 2009; accepted for publication Sep-tember 12, 2009.
Use of Simvastatin in Chronic Periodontitis Patients Volume 81 • Number 2
