Locally delivered minocycline microspheres for the treatment of periodontitis in smokers

Locally delivered minocyclinemicrospheres for the treatment ofperiodontitis in smokers

David Paquette1, Richard Oringer2,Jan Lessem3, Steven Offenbacher1,Robert Genco4, G. Rutger Persson5,Edward A. Santucci3 and Ray C.Williams1

1Department of Periodontology, University of

North Carolina, Chapel Hill, NC, USA;2Department of Periodontics, School of

Dental Medicine, SUNY-Stony Brook,

Stony Brook, NY, USA; 3OraPharma Inc.,

Warminster, PA, USA; 4Department of Oral

Biology, School of Dental Medicine,

SUNY-Buffalo, Buffalo, NY, USA;5Department of Periodontics, Regional

Clinical Dental Research Center, University

of Washington, Seattle, WA, USA

Paquette D, Oringer R, Lessem J, Offenbacher S, Genco R, Persson GR, Santucci EA,Williams RC: Locally delivered minocycline microspheres for the treatment ofperiodontitis in smokers. J Clin Periodontol 2003; 30: 787–794. r BlackwellMunksgaard, 2003.

AbstractAim: The aim of the present analysis of a larger phase 3 clinical trial was to evaluatethe efficacy of 1mg minocycline hydrochloride microencapsulated in 3mg ofresorbable polymer, subgingivally administered as an adjunct to scaling and rootplaning (SRP) in smokers with chronic periodontitis.

Material and Methods: Two hundred and seventy-one patients who smoked wererandomized to one of three treatment groups: (1) SRP alone, (2) SRP plus vehicle(polymer without minocycline) or (3) SRP plus minocycline microspheres. Full mouthSRP was performed for all groups at baseline, and vehicle or minocyclinemicrospheres were administered to the appropriate patients at all periodontalpockets X5mm at baseline, 3 and 6 months. Efficacy was evaluated over9 months.

Results: Significantly greater pocket depth reductions with SRP plus adjunctiveminocycline microsphere treatment were observed at 1, 6 and 9 months (po0.05)versus control treatments. At 9 months, smokers treated with SRP plus minocyclinemicrospheres exhibited a pocket depth reduction of 1.19mm from baseline, ascompared to 0.90mm for smokers treated with SRP alone. The efficacy of adjunctiveminocycline microspheres was consistent among all tested smoking subcohorts,including those based on gender, age and smoking exposures.

Conclusion: These data indicate that treatment with SRP plus locally deliveredminocycline microspheres is more effective than SRP alone in reducing pocket depthsin smokers with periodontitis.

Key words: smoking; minocycline/therapeuticuse;periodontitis/drug therapy;clinical trial

Accepted for publication 12 November 2002

Smoking continues to be a prevalentrisk behavior and contributor to popula-tion morbidity and mortality (Boyle1997, American Cancer Society 2000,Johnson 2001, Viegi et al. 2001, Villa-blanca et al. 2000). Smoking behaviorsalso confer a substantial risk fordestructive periodontitis, a principalcause for tooth loss in humans (Tonetti1999, Haffajee & Socransky 2001).Data from a number of case controlstudies indicate that smokers are 2.6–6times more likely to exhibit destructiveperiodontitis versus nonsmokers (Amer-ican Academy of Periodontology Re-search, Science and Therapy Committee1999). In addition, a linear relationship

is observed between the prevalence ofmoderate to advanced periodontitis andsmoking exposure measured in dailycigarettes, cumulative years and serumcotinine levels (Haber et al. 1993,Grossi et al. 1994, 1995a, Gonzalez etal. 1996). Recently, Krall et al. (1999)assessed tooth loss and alveolar boneloss among 690 dentate male partici-pants in the Veterans AdministrationLongitudinal Aging Study. This 23-yearcohort study documented significantrelative risks of 1.6, 1.3 and 1.6 fortooth loss among cigarette, cigar andpipe smokers, respectively. Further-more, an increased incidence of pro-gressive alveolar bone loss was

observed radiographically for smokersrelative to nonsmokers.

Not only are smokers at higher riskfor destructive periodontitis, but theyalso respond less favorably to conven-tional or mechanical interventions ascompared to nonsmokers. The majorityof longitudinal cohort studies indicatethat smokers exhibit smaller probingpocket depth reductions and smallerclinical attachment level gains follow-ing nonsurgical scaling and root planing(SRP) (Preber & Bergstrom 1986, New-man et al. 1994, Grossi et al. 1995b,Preber et al. 1995, Haffajee et al. 1997).Smokers also exhibit poorer long-termresponses in maintenance therapy

J Clin Periodontol 2003; 30: 787–794 Copyright r Blackwell Munksgaard 2003Printed in Denmark. All rights reserved

(McGuire & Nunn 1996). For example,Ah et al. (1994) have reported thatsmokers tend to exhibit periodontitisrecurrence over 6 years with supportiveperiodontal therapy. In contrast, non-smokers remain relatively stable withmaintenance therapy. Additionally,MacFarlane et al. (1992) and Magnusson& Walker (1996) have noted that over90% of periodontitis patients historicallyclassified as ‘‘refractory’’ to therapypresent with smoking behaviors.

Smokers therefore constitute a pre-valent and therapeutically challengingsubpopulation of patients with period-ontitis. In a recent phase 3 clinical trial,Williams et al. (2001) demonstratedthe efficacy of minocycline hydrochloridemicroencapsulated in a resorbable polymer(polyglycolide-co-dl-lactide) (ArestinTM,Orapharma, Inc., Warminster, PA, USA)and applied subgingivally as an adjunct toSRP in patients with chronic periodontitis.Following the primary analysis and pub-lication of results, we wondered if smok-ing would diminish the efficacy of locallydelivered minocycline microspheres.Therefore, we have focused on thesubpopulation of patients who smoked inthis report and examined the efficacy ofminocycline microspheres in this ‘‘at risk’’group.

Material and Methods

Two hundred and forty-eight subjectswho smoked and who exhibited moder-ate to advanced chronic periodontitiswere recruited among 18 centers. Smo-kers who self-reported using tobaccoproducts within the last 6 months of thescreening visit were identified. Toqualify for overall study enrollment,subjects, 30 years of age or older,presented in good general health, butdenied any heart murmur, valvulardisease, prosthetic joint replacement,chronic or active infectious disease orallergy to tetracyclines. Additionally,patients denied any use of antibiotics,phenytoin, calcium antagonists, cyclos-porine, warfarin sodium, aspirin ornonsteroidal anti-inflammatory drugs(NSAIDs) within 1 month of screening.Subjects of both sexes were included;however, female subjects were excludedif they were pregnant, lactating or didnot practice adequate birth control.Qualifying periodontitis subjects exhib-ited at least four teeth with probingdepths of 6–9mm and bleeding onprobing. All participants provided writ-

ten informed consent under the approvalof each center’s Institutional ReviewBoard.

The study design for this single-blinded, phase 3 clinical trial featuredthree parallel treatment arms: (1) SRPalone (control), (2) SRP plus adjunctivevehicle (polymer without the activeagent or placebo control) or (3) SRPplus adjunctive minocycline micro-spheres (experimental group). At base-line, all subjects received full mouthSRP, which was unrestricted with re-spect to time or use of local anesthesia,ultrasonics or hand instruments. SRPwas completed at one or two appoint-ments within a 2-week period. There-after, subjects received either noadditional therapy or additional adjunc-tive therapies (vehicle or minocyclinemicrospheres as per the randomizationscheme and stratified by the center).Vehicle or minocycline microsphereswere administered to the appropriategroups at all periodontal pockets mea-suring 5mm or more at baseline. Noadditional mechanical instrumentationwas performed for patients over the next9 months. Adjunctive vehicle or mino-cycline microspheres were re-adminis-tered at 3 months and 6 months at thesame periodontal pockets identified atbaseline.

Clinical examiners, blinded withrespect to treatment assignment, as-sessed efficacy with probing parametersat baseline, 3, 6 and 9 months. Prior totrial initiation, all examiners werecalibrated for probing parameters,and intra-class coefficients or reliabilityvalues ranged from 0.81 to 0.98. Theprimary outcome variable for the trialwas probing depth, measured from thegingival margin to the base of theperiodontal pocket using a Universityof North Carolina #15 periodontal probe(Hu-Friedy Manufacturing Company,Chicago, IL, USA) and recorded inwhole millimeters. Measurements wereobtained at six sites per tooth androunded down to the nearest millimeter.To minimize measurement and record-ing errors, a multiple pass strategy wasemployed such that two full mouthprobings were performed at each ex-amination visit. If the two probing depthmeasures differed by 2mm or more at aparticular site, a third probing measurewas obtained. In the analysis, the closertwo of the probing depth measures wereaveraged for each site and at each timepoint. Secondary efficacy outcomeswere also collected and included clin-

ical attachment level and bleeding onprobing. Clinical attachment level wascalculated in millimeters as the differ-ence of pocket depth minus recession,and bleeding was scored as present orabsent within 10 s following the firstprobing pass.

Clinical data were analyzed usingSAS software (Research Triangle Park,NC, USA), and the subject as the unit ofmeasure. Subject means and responsesincluded all periodontal pockets identi-fied at baseline (X5mm). Responsedifferences were evaluated for all sub-jects randomized at baseline (intent-to-treat population). If a subject withdrewprematurely from the trial, the lastobservation was carried forward byconvention. Site-specific changes inprobing parameters from baseline wereaveraged to provide an overall patientmean change. To test for differencesamong groups, patient mean changeswere assessed using an analysis ofcovariance model adjusted for studycenter, baseline periodontitis severityand age. Given overall significance atthe po0.05 level, pairwise comparisons(experimental versus control) were per-formed using two-sided t-tests. In addi-tion, descriptive statistics on baselinedemographics were tabulated, andsmoking experience was quantified inpack-years (i.e., number of cigarettepacks smoked per day times the numberof years smoked, where one pack equals20 cigarettes).

Results

Of the 271 recruited smokers, 91 wererandomized to SRP alone, 90 to SRPplus vehicle and 90 to SRP plusminocycline microspheres. Groups werebalanced with respect to study with-drawals. Three smokers per treatmentgroup either withdrew consent to parti-cipate before 9 months or were with-drawn by the investigator due to lack ofcompliance or periodontitis worsening(e.g., periodontal abscess formationnecessitating peroral antibiotics).

Demographic and baseline character-istics were similar among the threerandomized treatment groups (Table1). Enrolled smokers were predomi-nantly male (56.1%), younger than 50years (73.4%) and Caucasian (81.2%).Overall, 41.1%–48.4% of smokers pergroup were classified as exhibitingadvanced chronic periodontitis (versusmoderate chronic periodontitis). The

788 Paquette et al.

groups also appeared to be comparablefor overall smoking exposures. Meansmoking exposures ranged from 20.8 to22.6 pack-years per group (Table 1).Approximately one-third of smokersself-reported 20 or more pack-years oftobacco use (Fig. 1).

Changes in probing depth over the 9-month trial are presented in Figure 2 forthe smoker population. Following SRPplus a single administration of minocy-cline microspheres, smokers exhibitedsignificant probing pocket depth reduc-tions at 1 month as compared tosmokers treated with SRP alone(p5 0.013) or smokers treated withSRP plus vehicle (p5 0.015). Accord-ingly, a 1.11mm pocket depth reductionwas observed at 1 month in adjunctiveminocycline microsphere patients ver-sus 0.92mm reductions in patientstreated with SRP alone or SRP plusvehicle. Greater pocket depth reductionswere maintained at 3 months within theminocycline microsphere-treated pa-tients; however, the response differ-ences between the experimental groupand the positive and placebo controlsreached only borderline significance(p5 0.081 and 0.055, respectively).With reapplication of minocycline mi-crospheres at 3 months, smokers in theexperimental group again exhibitedsignificant pocket depth reductions(1.20mm) over SRP alone (0.90mm,po0.001) or SRP plus vehicle(1.02mm, p5 0.038). We have pre-viously reported that smokers at 9months treated with adjuctive minocy-cline microspheres demonstrated a sig-nificantly greater mean pocket depthreduction (1.19mm) as compared topatients treated with SRP alone(0.91mm, p40.002) or SRP plus vehi-cle (0.91mm, p40.045) (Williams etal. 2001). The response differencebetween SRP plus minocycline micro-spheres and SRP alone groups was evenmore pronounced in patients identifiedwith severe chronic periodontitis andwho exhibited overall mean probingpocket depthsX6.00mm at baseline.Significant differences were detectedamong these treatment subgroups at 9months (po0.05), where a 0.52mmdifference in pocket depth responseswas observed between smokers withsevere disease treated with adjunctiveminocycline microsphere and thosetreated with SRP alone.

When smokers were segregated onthe basis of cumulative tobacco expo-sures (Fig. 3), the mean pocket depth

reduction was greater in almost everypack-year subgroup for SRP plus min-ocycline microspheres than that for thetwo control treatments. This responsedifference appeared to be most pro-nounced among those patients reportingusage of tobacco between 11 and 20years of tobacco use. Likewise whengender was considered, male smokersexhibited greater probing depth re-sponses with adjunctive minocycline

microspheres as compared to the overallpatient population (Fig. 4). Male smo-kers treated with adjunctive minocy-cline microspheres exhibited significantpocket depth reductions at 6 and 9months (p5 0.004 and 0.012, respec-tively) as compared to male smokerstreated with SRP alone. Female smokerstreated with adjunctive minocyclinemicrospheres exhibited higher meanpocket depth reductions as compared

Table 1. Patient demographic and baseline characteristics; smoker groups were comparable withregard to gender age, ethnicity, smoking exposure and periodontitis status

Treatment Arm SRP alone Vehicle1SRP MinocyclineMicrospheres1SRP

Sample size 91 90 90GenderMale 52 (57.1%) 54 (60.0%) 46 (51.1%)Female 39 (42.9%) 36 (40.0%) 44 (48.9%)

Mean age years (SE) 46.0 (4.8) 45.5 (4.8) 46.5 (4.9)450 years 70 (76.9%) 67 (74.4%) 62 (68.9%)450 years 21 (23.1%) 23 (25.6%) 28 (31.1%)

EthnicityCaucasian 70 (76.9%) 76 (84.4%) 74 (82.2%)African American 12 (13.2%) 10 (11.1%) 10 (11.1%)Asian American 0 (0.0%) 0 (0.0%) 1 (1.1%)Hispanic 6 (6.6%) 4 (4.4%) 5 (5.6%)Other 3 (3.3%) 0 (0.0%) 0 (0.0%)

Mean pack years 20.8 26.7 22.6

Mean baseline probingoutcomes (SE)Pocket depth (mm) 5.8470.04 5.8670.04 5.8070.04Clinical attachmentlevel (mm)

5.6270.05 5.5470.06 5.5270.05

Periodontitis severityModerate (AAP III) 47 (51.6%) 53 (58.9%) 47 (52.2%)Advance (AAP IV) 48 (48.4%) 37 (41.1%) 43 (47.8%)

Fig. 1. Percentage of smokers (SRP and adjunctive minocycline microsphere groups only) bysmoking exposures in pack-years; most smokers reported at least a 20-pack-year smokinghistory.

Efficacy of minocycline microspheres in smokers 789

to SRP alone for all post-treatment timepoints (data not shown), but significancewas reached at 1 month only (po0.05).Among smokers older than 50 years ofage (Fig. 5), significant 0.52 and0.59mm differences in pocket depthreductions were noted between minocy-cline microsphere patients and SRPalone patients at 6 and 9 months,respectively (po0.05). Cumulatively,these data indicate the consistent effec-tiveness of SRP plus minocycline mi-

crospheres among relevant smokersubcohorts.

In patients who smoked, 17% moreperiodontal pockets treated with adjunc-tive minocycline microsphere groupresponded with pocket depth reductionsX2mm at 9 months as compared topockets in smokers treated with SRPalone (Figs. 6, 7). This increased re-sponse incidence with adjunctive mino-cycline microspheres was also observedwhen smokers with cardiovascular dis-

ease or molar sites were considered inthe analysis. Similarly, 10% moreperiodontal pockets in the adjunctiveminocycline microsphere group re-sponded with a pocket depth reductionX3mm at 9 months (data not shown).In all studied subgroups, a higherproportion of pockets treated with SRPplus minocycline microspheres demon-strated reductions of 2mm or more ascompared to SRP alone. For malesmokers over 50 years of age, 60%more pockets responded with reductionsX2mm (baseline to 9 months).

Treatments in general improved thesecondary outcomes, clinical attach-ment level and percent bleeding onprobing; however, in smokers no statis-tically significant differences werenoted among the three smoker-treatmentgroups over the monitoring period forthese outcomes.

Discussion

The data presented in this report de-monstrate that locally delivered mino-cycline microspheres used with SRPreduce mean pocket depth significantlymore than SRP alone in chronic period-ontitis patients who smoke. In thisstudy, smokers were defined using aself-reported questionnaire, similar toother studies (Gelskey 1999, Ryder etal. 1999, Tomar & Asma 2000). Parti-cipating smokers treated with a singleadministration of minocycline micro-spheres exhibited a 21% greater pocketdepth reduction at 1 month as comparedto smokers treated with SRP alone. Wealso observed 33% and 32% greaterpocket depth reductions at 6 and 9months, respectively, following SRPplus multiple applications of minocy-cline microspheres in smokers. Thepercent improvements with adjuctiveminocycline microspheres among thesmoking subpopulation are higher thanthose reported by Williams et al. (2001)for the larger population of both non-smokers and smokers (e.g., 22% greaterpocket depth reduction at 9 months).Indeed, the difference in probing depthreduction between SRP and minocy-cline microspheres and SRP aloneamong smokers at 9 months was0.29mm, which was slightly greaterthan that recorded for the overallpopulation (i.e., 0.24mm). Since theoverall, nonsmoking and smoking po-pulations were comparable with respectto baseline periodontitis severity, the

Fig. 2. Changes from baseline in mean (SE) pocket depth in smokers treated with adjunctiveminocycline microspheres, vehicle or SRP alone; statistically significant differences(po0.05) were detected between smokers treated with minocycline microspheres andcontrols at 1, 6 and 9 months.

Fig. 3. Mean pocket depth reduction (baseline to 9 months) by smoking exposure andtreatment; for all smoking exposure categories, smokers treated with adjunctive minocyclinemicrospheres exhibited greater mean pocket depth reductions.

790 Paquette et al.

heightened response among smokerstreated with adjunctive minocyclinemicrospheres did not appear to be dueto any increase in case severity. Onaverage, smokers in the control grouptreated with SRP alone exhibited smal-ler clinical improvements at all timepoints as compared to their nonsmokingcounterparts (data not shown); never-theless, with adjunctive minocyclinemicrosphere therapy, the responseamong smokers was comparable to that

seen for nonsmokers treated with SRPalone. The clinical improvements withadjunctive minocycline microsphereswere consistent among all tested smokersubcohorts, including those based ongender, age and cumulative smokingexposures. Indeed, the responses forboth smokers and nonsmokers arearguably clinically significant in thatperiodontitis patients treated with min-ocycline microspheres are 60% morelikely to shift to a more maintainable

case definition (mean PDo5mm) (Wil-liams et al. 2001). This analysis onsmokers and the larger trial were notpowered a priori to detect significantchanges in secondary outcomes likeclinical attachment level and bleedingon probing. These data neverthelessindicate that adjunctive minocyclinemicrospheres are efficacious in reducingpocket depth in smokers with period-ontitis more than SRP alone.

Other investigative groups have re-ported on the effects of locally deliveredtetracyclines in periodontitis patientswho smoke. Mombelli et al. (1997)assessed the responses to tetracyclinefiber therapy (25% in an ethylene vinylacetate polymer, two pockets per sub-ject) alone versus tetracycline fibertherapy plus SRP (whole mouth) in 19chronic periodontitis patients, four ofwhom were smokers. Smokers in thissmall study exhibited significantly lessreduction in probing depth and less gainin clinical attachment as compared tononsmokers. Kinane & Radvar (1997)conducted a similar trial in which 28smokers and 26 nonsmokers with peri-odontitis were randomized to SRPalone, SRP plus tetracycline fiber, SRPplus metronidazole gel (25% in a mono-and triglyceride vehicle) or minocyclinegel (2% ointment). The study monitoredchanges in probing parameters frombaseline to 6 weeks, but did not attemptto separate the multiple treatment mod-alities. In general, smokers responded totreatments with significantly smallerpocket depth reductions versus nonsmo-kers (0.76 versus 1.14mm, respec-tively). No differences in clinicalattachment level gains were detectedbetween smoking and nonsmoking co-horts. When a linear regression analysiswas performed, a significant relation-ship was noted between baseline pocketdepth and treatment responses for non-smokers, but not for smokers. Recently,Ryder et al. (1999) examined the effectsof SRP alone versus doxycycline hy-clate gel (10% in a polylactic acidpolymer) alone in 121 current smokers,137 former smokers and 100 nonsmo-kers. Although nonsmokers treated withSRP alone exhibited the greatest PD andCAL improvements on average, nosignificant differences between SRPand doxycycline hyclate monotherapywere detected for current smokers at9 months. The trials cited above onlocally delivered tetracyclines do reiter-ate the poorer treatment responses seenin smokers with periodontitis. These

Fig. 4. Changes from baseline in mean (SE) pocket depth in male smokers treated withadjunctive minocycline microspheres, vehicle or SRP alone; statistically significantdifferences (po0.05) were detected between male smokers treated with minocyclinemicrospheres and controls at 6 and 9 months.

Fig. 5. Changes from baseline in mean (SE) pocket depth in smokers older than 50 years andtreated with adjunctive minocycline microspheres, vehicle or SRP alone; statisticallysignificant differences (po0.05) were detected between older smokers treated withminocycline microspheres versus controls at 6 and 9 months.


studies do, however, differ from thepresent trial of minocycline micro-spheres on the basis of study powerand equivalency monotherapy claimsversus superiority adjunctive claims.

The adjunctive efficacy of minocy-cline microspheres in smokers demon-strated with this analysis may becredited to the active agent’s inhibitionof both the flora and potential reduc-tions in the destructive host response.Although this report did not include anyantimicrobial assessment in smokers,previous phase 1 and 2 trials indicateeffective local concentrations of mino-cycline for at least 21 days andsignificant reductions in periodontalpathogens like P. gingivalis at 30 daysfollowing a single administration (un-published data). In addition, as amember of the tetracyclines, minocy-cline blocks matrix metalloproteinases

and can inhibit periodontitis progressionindependent of their antimicrobial prop-erties (Golub et al. 1983, 2001).Furthermore, Oringer et al. (2002) haverecently shown that SRP plus minocy-cline microspheres significantly de-crease crevicular fluid levels ofpyrodinoline cross-linked carboxy-terminal telopeptide of Type I collagen(ICTP), a surrogate marker of boneresorption and matrix matalloproteinaseactivity.

Based on the current findings fromthis study, it can be concluded thatlocally delivered minocycline micro-spheres administered with SRP are moreefficacious in reducing pocket depth ascompared to SRP alone in smokers withchronic periodontitis. While cliniciansshould continue to emphasize smokingcessation to patients, SRP plus minocy-cline microspheres are appropriate sec-

ondary interventions for patients in theprocess of quitting or who refuse to quit.Future research should clarify the phar-macodynamics of minocycline micro-spheres in this important riskpopulation.

Acknowledgements

We acknowledge and thank the follow-ing investigators who were part of thestudies: Donald Adams (Oregon HealthScience University, Portland, OR,USA), Gary Armitage (University ofCalifornia, San Francisco, CA, USA),Jack Caton (Eastman Dental Center,Rochester, NY, USA), David Cochran(University of Texas at San Antonio,San Antonio, TX, USA), Connie Drisko(University of Louisville, Louisville,KY, USA), Joseph Fiorellini (HarvardSchool of Dental Medicine, Boston,MA, USA), William Giannobile ( Uni-versity of Michigan, Ann Arbor, MI,USA), Georgia Johnson (University ofIowa, Iowa City, IO, USA), WilliamKilloy (University of Missouri at Kan-sas City, Kansa City MO, USA), IraLamster (Columbia University, NewYork, NY, USA), Ingvar Magnusson(University of Florida, Gainesville,USA), Sigmund Socransky (ForsythDental Center, Boston, MA, USA),Thomas VanDyke (Boston University,Boston, MA) and Larry Wolff (Uni-versity of Minnesota, Minneapolis, MN,USA).

Zusammenfassung

Lokal abgegebene Minocyclin-Microspherenzur Behandlung von Parodontitis bei RauchernAim: Das Ziel der vorliegenden Analyse einerumfangreichen Phase-3-Untersuchung war es,bei Rauchern mit chronischer Parodontitis dieEffizienz von 1 mg Minocycline-Hydrochlorid,welches in 3mg resorbierbarem Polymer mik-roverkapselt ist und subgingival zusatzlich zuScaling und Wurzelglattung appliziert wird, zuevaluieren.Material and Methods: 271 Patienten, dieRaucher waren, wurden randomisiert auf einevon 3 Behandlungsgruppen verteilt: (1) nurScaling und Wurzelglattung (SRP), (2) SRP undVehikel (Polymer ohne Minocyclin) oder (3)SRP und Minocyclin-Microspheren. Bei derEingangsuntersuchung wurde fur alle Gruppenim gesamten Gebi� ein Scaling und Wurzel-glattung durchgefuhrt. Bei der Eingangsunter-suchung, sowie nach 3 und 6 Monaten wurdebei den entsprechenden Patienten das Vehikeloder Minocyclin-Microspheren in allen paro-dontalen Taschen, welche X5mm Sondierung-stiefe aufwiesen, appliziert.Results: Im Vergleich zu dem Kontrollbehan-dlungen wurde bei der SRP kombiniert mit

Fig. 6. Percentage of sites responding with pocket depth reductions X2mm (baseline to9 months) for all smokers and subcohorts.

Fig. 7. Difference in percent of sites responding with pocket depth reductions X2mm(baseline to 9 months) for all smokers and subcohorts treated with minocycline microspheresversus SRP alone.

792 Paquette et al.

adjuvanter Minocyclin-Microspheren-Behan-dlung nach 1, 6 und 9 Monaten (po0.05) einesignifikant hohere Reduktion der Taschentiefebeobachtet. Nach 9 Monaten zeigten Raucher,die mit SRP kombiniert mit Minocyclin-Micro-spheren behandelt wurden bezuglich der Aus-gangssituation eine Taschenreduktion von1.19mm verglichen mit 0.90mm fur dieRaucher, die nur mit SRP behandelt wurden.Die Effizienz von adjuvanter Minocyclin-Mi-crospheren-Behandlung war bei allen getestetenRaucher-Unterkohorten, einschlie�lich der aufGrundlage von Geschlecht, Alter und Dauer desRauchens, ubereinstimmend.Schlussfolgerung: Diese Daten zeigen, dass beiRauchern mit Parodontitis die Behandlungmit SRP plus lokal applizierten Minocyclin-Microspheren hinsichtlich der Reduktionder Taschentiefe effektiver ist als alleinigesSRP.

Resume

Microspheres de minocycline places in situpour le traitement de la parodontite chez lesfumeursLes fumeursont en general une parodontite plussevere et repondent moins favorablement autraitement que les non-fumeurs. Le but del’analyse presente d’un essai clinique de phase-3 a ete d’evaluer l’efficacite d’un polymereresorbable de 3mg encapsulant1 mg d’hydro-chloride de minocycline administre en sous-gingival en association avec le detartrage et lesurfacage chez des fumeurs avec parodontitechronique. Deux cent septante et un fumeursont ete repartis dans un des trois groupes detraitement suivants: (1) detartrage et surfacageradiculaire seuls (SRP), (2) SRP 1 le vehicule(polymere sans minocycline) et (3) SRP 1 lesmicrospheres de minocycline. Un detartrage etun surfacage radiculaire de l’ensemble de lacavite buccale ont ete effectues chez tous lespatients lors l’examen initial et le vehicule ou laminocycline ont ete places chez certainspatients au niveau de toutes les poches5 5mmau depart et apres trois et six mois. L’efficacitea ete evaluee apres neuf mois. Des reductionsde poches significativement plus importantesavec le SRP1la minocycline ont ete observeesapres un, six et neuf mois (po0.05) vs lestraitements controles. Apres neuf mois, lesfumeurs traites par SRP1minocycline exhibai-ent une reduction de la profondeur de poche de1.19mm vis-a-vis de l’examen initial compare a0.90mm pour les fumeurs traites seulement parSRP. L’efficacite des microspheres de minocy-cline en association avec SRP etait concreteparmi tous les fumeurs quels que soient le sexe,l’age et le niveau de tabagisme. Ces donneesindiquent que le traitement SRP 1 minocyclineest plus efficace que le SRP seul a reduire laprofondeur des poches chez les fumeurs avecparodontite.

References

Ah, M. K. B., Johnson, G. K., Kaldahl, W. B.,

Pati, K. D. & Kalkwarf, K. L. (1994) The

effect of smoking on the response to period-

ontal therapy. Journal of Clinical Period-

ontology 21, 91–97.

American Academy of Periodontology Re-

search, Science and Therapy Committee

(1999) Tobacco use and the periodontal

patient. Journal of Periodontology 70,

1419–1427.

American Cancer Society (2000) Tobacco control

country profiles. Proceedings from the 11th

World Conference on Tobacco OR Health.

http://tobacco.who.int/page.cfm?pid=51.

Boyle, P. (1997) Cancer, cigarette smoking

and premature death in Europe: a

review including the recommendations

of European Cancer Experts Consensus

Meeting, Helsinki, October 1996. Lung

Cancer 17, 1–60.

Gelskey, S. C. (1999) Cigarette smoking and

periodontitis: methodology to assess the

strength of the evidence in support of a

casual association. Community Dentistry and

Oral Epidemiology 27, 16–24.

Golub, L. M., Lee, H. M., Lehrer, G., Nemisoff,

A., McNamara, T., Kaplan, R. & Ramma-

murthy, M. S. (1983) Minocycline reduces

gingival collagenolytic activity during

diabetes. Preliminary observations and

a proposed new mechanism of action.

Journal of Periodontal Research 18,

516–526.

Golub, L. M., McNamara, T. F., Ryan, M. E.,

Kohut, B., Blieden, T., Payonk, G., Sipos, T.

& Baron, H. J. (2001) Adjunctive treat-

ment with subantimicrobial doses of

doxycycline: effects on gingival fluid

collagenase activity and attachment loss

in adult periodontitis. Journal of Clinical

Periodontology 28, 146–156.

Gonzalez, Y. M., De Nardin, A., Grossi, S. G.,

Machtei, E. E., Genco, R. J. & De Nardin, E.

(1996) Serum cotinine levels, smoking, and

periodontal attachment loss. Journal of

Dental Research 75, 796–802.Grossi, S. G., Genco, R. J., Machtei, E. E., Ho,

A. W., Koch, G., Dunford, R., Zambon, J. J.

& Hausmann, E. (1995a) Assessment of risk

for periodontal disease. II. Risk indicators for

alveolar bone loss. Journal of Periodontology

66, 23–9.Grossi, S. G., Skrepcinski, F. B., Decaro, T.,

Zambon, J. J., Cummins, D. & Genco, R. J.

(1995b) Response to periodontal therapy in

diabetics and smokers. Journal of Period-

ontology 67, 1094–1102.

Grossi, S. G., Zambon, J. J., Ho, A. W., Koch,

G., Dunford, R. G., Machtei, E. E., Norderyd,

O. M. & Genco, R. J. (1994) Assessment of

risk for periodontal disease. I. Risk indicators

for attachment loss. Journal of Periodontol-

ogy 65, 260–267.

Haber, J., Wattles, J., Crowley, M., Mandell, R.,

Joshipura, K. & Kent, R. L. (1993) Evidence

for cigarette smoking as a major risk factor

for periodontitis. Journal of Periodontology

64, 16–23.

Haffajee, A. D., Cugini, M. A., Dibart, S.,

Smith, C., Kent, R. L. Jr. & Socransky, S. S.

(1997) The effect of SRP on the clinical and

microbiological parameters of periodontal

diseases. Journal of Clinical Periodontology

24, 324–334.

Haffajee, A. D. & Socransky, S. S. (2001)

Relationship of cigarette smoking to attach-

ment level profiles. Journal of Clinical

Periodontology 28, 283–295.Johnson, N. (2001) Tobacco use and oral

cancer: a global perspective. Journal of

Dental Education 65, 328–339.

Kinane, D. F. & Radvar, M. (1997) The effect

of smoking on mechanical and antimicrobial

periodontal therapy. Journal of Periodontol-

ogy 68, 467–472.

Krall, E. A., Garvey, A. J. & Garcia, R. I.

(1999) Alveolar bone loss and tooth loss

in male cigar and pipe smokers. Journal

of the American Dental Association 130,

57–64.

MacFarlane, G. D., Herzberg, M. C., Wolff, L.

F. & Hardie, N. A. (1992) Refractory

periodontitis associated with abnormal poly-

morphonuclear leukocyte phagocytosis and

cigarette smoking. Journal of Periodontology

63, 908–913.Magnusson, I. & Walker, C. B. (1996) Refrac-

tory periodontitis or recurrence of disease.

Journal of Clinical Periodontology 23,

289–292.

McGuire, M. K. & Nunn, M. E. (1996)

Prognosis versus actual outcome. III. The

effectiveness of clinical parameters in accu-

rately predicting tooth survival. Journal of


Mombelli, A., Lehmann, B., Tonetti, M. &

Lang, N. P. (1997) Clinical response to

local delivery of tetracycline in relation to

overall and local periodontal conditions.


470–477.

Newman, M., Kornman, K. & Holtzmann, S.

(1994) Association of clinical risk factors

with treatment outcomes. Journal of Period-

ontology 65, 489–497.Oringer, R. J., Al-Shammari, K. F., Aldredge,

W. A., Iacono, V. J., Eber, R. M., Wang, H.

L., Berwald, B., Nejat, R. & Giannobile, W.

V. (2002) Effects of locally delivered

minocycline microspheres on markers of

bone resorption. Journal of Periodontology

73, 835–842.

Preber, H. & Bergstrom, J. (1986) The effect

of non-surgical treatment on periodontal

pockets in smokers and non-smokers.


319–323.

Preber, H., Linder, L. & Bergstrom, J. (1995)

Periodontal healing and periopathogenic

microflora in smokers and non-smokers.


946–952.

Ryder, M. I., Poas, B., Adams, D., Beiswanger,

B., Blanco, V., Donly, K., Hallmon, W.,

Hancock, E. B., Hanes, P., Hawley, C.,

Johnson, L., Wang, H. L., Wolinsky, L.,

Yukna, R., Polson, A., Carron, G. & Garrett,

S. (1999) Effects of smoking on local

delivery of controlled-release doxycycline

as compared to scaling and root planing.


681–691.


Tomar, S. L. & Asma, S. (2000) Smoking –

attributable periodontitis in the United States:

findings from NHANES III. Journal of


Tonetti, M. S. (1999) Cigarette smoking and

periodontal diseases: etiology and manage-

ment of disease. Annals of Periodontology 3,

88–101.

Viegi, G., Scognamiglio, A., Baldacci, S.,

Pistelli, F. & Carrozzi, L. (2001) Epidemiol-

ogy of chronic obstructive pulmonary disease

(COPD). Respiration 68, 4–19.

Villablanca, A. C., McDonald, J. M. &

Rutledge, J. C. (2000) Smoking and cardio-

vascular disease. Clinics in Chest Medicine

21, 159–172.Williams, R., Paquette, D., Offenbacher, S.,

Adams, D., Armitage, G., Bray, K., Caton, J.,

Cochran, D., Drisko, C., Fiorellini, J.,

Giannobile, W., Grossi, S., Guerrero, D.,

Johnson, G., Lamster, I., Magnusson, I.,

Oringer, R., Persson, G. R., VanDyke, T.,

Wolff, L., Santucci, E. A., Rodda, B. E. &

Lessem, J. (2001) Treatment of periodontitis

by local administration of minocycline mi-

crospheres: a controlled trial. Journal of


Address:

David W. Paquette

Department of Periodontology

Center for Oral and Systemic Diseases

University of North Carolina School

of Dentistry

Brauer Hall, CB #7450

Chapel Hill, NC 27599-7450

USA

Fax: 11 919 966 0284

E-mail: [email protected]

794 Paquette et al.

Locally delivered minocycline microspheres for the treatment of periodontitis in smokers

Documents

Transcript of Locally delivered minocycline microspheres for the treatment of periodontitis in smokers