Braz Dent J 19(4) 2008

Effect of COX-2 selective inhibitor in periodontal treatment 323Braz Dent J (2008) 19(4): 323-328

Correspondence: Prof. Dr. Mario Taba Jr., Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Avenida do Café S/N,14040-904 Ribeirão Preto, SP, Brasil. Tel: +55-16-3602-3980. Fax: +55-16-3602-4788. e-mail: mtaba@usp.br

ISSN 0103-6440

Short-Term Effect of COX-2 Selective Inhibitor asan Adjunct for the Treatment of Periodontal

Disease - A Clinical Double-Blind Study in Humans

Márcia de Noronha PINHOLeonardo Bíscaro PEREIRA

Sérgio Luís Scombatti de SOUZADaniela Bazan PALIOTO

Márcio Fernando de Moraes GRISIArthur Belém NOVAES JR.

Mario TABA JR.

Department of Oral and Maxillofacial Surgery and Traumatology and Periodontology,Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

Adjunctive therapeutic strategies that modulate the inflammatory mediators can play a significant role in periodontal therapy. In thisdouble-blind, placebo-controlled study, 60 subjects diagnosed as periodontitis patients were evaluated for 28 days after periodontaltreatment combined with selective cyclooxygenase-2 (COX-2) inhibitor. The experimental group received scaling and root planning(SRP) combined with the Loxoprofen antiinflammatory drug (SRP+Loxoprofen). The control group received SRP combined withplacebo (SRP+placebo). Plaque index (PI), probing pocket depth (PD) and bleeding on probing (BOP) were monitored with anelectronic probe at baseline and after 14 and 28 days. Both groups displayed clinical improvement in PD, PI and BOP. They alsoshowed statistically similar values (p>0.05) of PD reduction on day 14 (0.4 mm) and on day 28 (0.6 mm). At the baseline, few deepersites (7 mm) from SRP+Loxoprofen group were responsible and most PD reduction was observed after 14 days (p<0.05). Thepercentage of remaining deep pockets 7 mm) after 14 days in the SRP+Loxoprofen group was significantly lower (p<0.05) than inthe SRP+placebo group. Loxoprofen presents potential effect as an adjunct of periodontal disease treatment, but long-term clinicaltrials are necessary to confirm its efficacy.

Key Words: periodontitis therapy, prostaglandin, adjunctive therapy, inflammation.

INTRODUCTION

Periodontal disease is a high prevalent infectiousinjury caused by specific bacterial species. However,most of the tissue breakdown is indirectly caused by toxicbacterial products that trigger the host response. Host-derived enzymes known as matrix metalloproteinases(MMPs), changes in osteoclast activity by cytokines andother inflammatory mediators like prostanoids are respon-sible for most periodontal tissue destruction (1). Thecyclooxygenase (COX) products of the arachidonicacid or simply prostanoids (PGs) and tromboxane(TxB2) are produced by activated monocytes, platelets

and fibroblasts. Both PGs and TxB2 are strong vasoac-tive mediators and stimulators of bone resorption (1-3).

Several host modulatory agents have been inves-tigated in clinical trials. Non-steroidal antiinflammatorydrugs (NSAIDs), sub-antimicrobial dose of doxycy-cline and bisphosphonates or combination of drugs havebeen successfully used as an adjunct to non-surgicalmechanical periodontal therapy. The results of hostmodulation studies have shown that this approach maybe a potential target to reduce tissue destruction. NSAIDsblockade the pro-inflammatory cytokines; sub-dose ofdoxycycline blockades the metalloproteinases and thebisphosphonates blockade the osteoclast activity (4,5).

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The basis of antiinflammatory drugs in periodon-tal disease treatment is related to the control of prostag-landin E2 (PGE2) through the inhibition ofcyclooxygenase-2 (COX-2) enzyme. Higher levels ofPGE2 are associated with increased gingival inflamma-tion and alveolar bone loss (1,3,6,7). Therefore, thepurpose of this study was to evaluate a selective COX-2 inhibitor derived from phenylpropionic acid,Loxoprofen sodium, as an adjunct for periodontal dis-ease treatment, using probing pocket depth (PD) toverify the inflammation reduction.

MATERIAL AND METHODS

Sample Distribution and Study Design

This was a randomized, double-blind, placebo-controlled study, which used parallel inter-subjects anda split-mouth design. Sixty healthy non-smoking sub-jects with at least 20 teeth, ranging in age from 35-50years, who had two or more teeth with clinical attach-ment loss (CAL) 6 mm and one or more sites with PD5 mm were selected according to the establishedperiodontitis criteria. Exclusion criteria were: presenceof systemic diseases, pregnancy or nursing women,gastric ulcer, hypersensitivity to antiinflammatory drugs,use of antibiotic, corticoids, immunosuppressive drugsor any NSAIDs within the past three months.

The 60 patients were randomly assigned toexperimental and control groups. The experimentalgroup received periodontal treatment that consisted ofconventional scaling and root planning (SRP), usingultrasonic scaler (Bob-Cat, Dentsply/Cavitron, LongIsland City, NY, USA) and Gracey curettes (Hu-Friedy,Chicago, IL, USA) combined with 60 mg/day ofLoxoprofen (Loxonin; Sankyo Pharma Brasil Ltda,Barueri, SP, Brazil) during 28 days (SRP+Loxoprofen).The control group received the same SRP treatmentcombined with placebo (SRP+Placebo). Periodontaltreatment was performed in 2 phases by a blindedexperienced periodontist (BP). Randomly, half-mouthreceived one-session of SRP at the baseline and thecontra-lateral side of the mouth received one-session ofSRP on day 14 (Fig. 1).

Clinical Procedures, Measurements and Monitoring

At baseline, medical and dental histories were

recorded and the following clinical parameters weremeasured: PD measured at 6 sites/teeth using an elec-tronic probe (Florida Probe Corporation, Gainesville, Fl,USA); the percentage of sites with bleeding on probing(BOP) and the percentage of tooth surfaces with dentalplaque (PI) (Table 1). The patients received mechanicaltherapy (SRP), oral hygiene instruction and orientationabout medication. Coded medication or placebo pack-ages were supplied for the first 14 days. Then, at thesecond appointment, clinical measurements were re-corded and drug use was assessed by means of medi-cation package inspection and pills counting. Also, oralhygiene instruction was reinforced and the contra-lateral side of the mouth received SRP. Mechanicaltherapy was completed and the remaining medication orplacebo packages were supplied for the next 14 days. Atthe end of 28 days, all clinical measurements were re-taken by the same blinded operator and medication usewas reviewed.

Statistical Analysis

The clinical measurements per patient were as-sessed. The mean and standard deviations were calcu-lated and non-parametric analyses were performedusing statistical software (Statistica for Window;StatSoft, Inc., Tulsa, OK, USA). The number of sites

Figure 1. Study design and timeline. All 60 patients had theirclinical measurements recorded at baseline, 14 and 28 days.Scaling and root planning was performed in 2 sessions, half-mouth at the baseline and the remaining contra-lateral teeth after14 days. Two groups were determined based on the Loxoprofenor placebo intake as an adjunct to the non-surgical periodontaltherapy. Loxoprofen dosage was 60 mg/day during 28 days.Placebo pills were identical to the real medication to keep thepatients and operator blinded. Probing pocket depth (PD),Bleeding on probing (BP) and Plaque index (PI).

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Effect of COX-2 selective inhibitor in periodontal treatment 325

with initial PD < 4 mm, 4 < 7 mm and 7 mm per patientwere computed for further analysis. Mann-Whitneytest was used to compare the differences betweengroups (SRP+Loxoprofen and SRP+Placebo). Fried-man test compared differences among the time points(baseline, 14 and 28 days) in each group. Chi-squaretest was used for nominal variables. All statisticalanalysis considered the significant level of 5%. TheCohen’s d effect size was also calculated for furtherinterpretation of the observed statistical significance.

RESULTS

All 60 patients completed the study, presenting100% of medication compliance or placebo, and nocomplain of adverse reactions to the Loxoprofen therapy.Compliance was monitored at both recall and final examvisits by the assessment of the amount of medicationtaken from the original prescription package.

Baseline demographic characteristics of the pa-tients divided by groups are presented in Table 1. Therewere no statistically significant differences (p>0.05)between groups regarding the evaluated parameters atbaseline. The smaller and uniform amount of plaquerecorded in both groups after 14 and 28 days suggest

Table 1. Baseline parameters for SRP+Loxoprofen andSRP+Placebo groups. No statistically significant differences wereobserved between groups (p>0.05). Patients received theperiodontal treatment according to a random order (n=60). Therandomization was assured due to the arbitrary distribution ofthe coded medication or placebo.

Parameters Groups

SRP+Loxoprofen SRP+Placebo

Age (yrs) 41 ± 4 42 ± 5Age range 35-49 35-50Gender (male /female) 14/16 14/16Race (whites/non-whites) 21/9 18/12PD (mm) 2.6 ± 0.6 2.4 ± 0.6BP (%) 23.8 ± 10.0 23.6 ± 11.1PI (%) 61.0 ± 25.4 68.0 ± 27.0

PD = Probing pocket depth; BOP = Bleeding on probing; PI=Plaque index.

the high degree of patient compliance with the proposedprotocol.

The therapeutic approach used in this study,SRP+Loxoprofen or SRP+Placebo, promoted clinicalimprovement with statistically significant reduction(p<0.05) of PD and BOP during the evaluated intervals(between 0-14, 0-28 and 14-28 days). Regarding PI,the reduction was statistically significant (p<0.05)between 0-14 and 0-28 days, but not between 14-28days (p>0.05).

Although both groups showed clinical improve-ment, there were no statistically significant differences(p>0.05) in PD reduction between groups after 28days. SRP+Loxoprofen and SRP+Placebo groupsshowed a PD reduction of 0.4 mm on day 14. After 28days, the overall PD reduction for both groups was 0.6mm (p>0.05).

Comparative analyses of the sites that did notreceive SRP therapy in the first 14 days showed greater PDreduction than the control sites (no-SRP+placebo). Thisdifference was statistically significant (p<0.05) after 14days, suggesting the potential effect of the adjunctivetherapy, although not clinically relevant. PD reductionmean was 0.3 ± 1.0 mm for Loxoprofen therapy solely and0.2 ± 1.1 mm for control sites. On day 14, both groupsreceived SRP at the contra-lateral side of the mouthfollowed by supplementary dose of medication or placebofor the next 14 days.

Considering the patient as an experimental unit,there was no significant difference (p>0.05) in the PDreduction between patients that used the medication andthose that received placebo. The differences were notstatistically significant neither after 14 days nor after 28days of periodontal treatment combined with adjunctiveantiinflammatory therapy (p>0.05). On day 14, the PDreduction in sites with initial PD 7 mm, in theSRP+Loxoprofen group, (2.2 ± 2.0 mm) was statisticallygreater than in the SRP+placebo group (1.5 ± 1.8 mm)(p<0.05).

Figure 2 demonstrated that after 14 days, theremaining deep pockets 7 mm of the SRP+Loxoprofengroup was significantly lower than in the SRP+placebogroup (p<0.05). However, the effect size for the PDreduction observed in the study was very low (d<0.4),indicating that the result is not clearly relevant. After 28days, there were no statistically significant differences(p>0.05) in PD reduction among groups and the percent-age of remaining deep pockets were similar.

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DISCUSSION

This short-term study evaluated the effect ofLoxoprofen on the reduction of probing pocket depth.It was observed a limited suggestive potential for thetreatment of deep periodontal pockets. Nevertheless,the initial difference in PD reduction and the benefits onthe deeper periodontal pockets were insignificant after28 days or longer. Likewise, other studies (2,8,9) havefound no differences in PD reduction between placeboand NSAID group after 28 days.

When the PD reduction was evaluated consider-ing the initial measurements of PD, the deeper periodon-tal pockets showed additional improvement in the first14 days after the SRP+Loxoprofen therapy. Moreover,in the SRP+Loxoprofen group the percentage of re-maining periodontal pockets 7 mm was significantlyreduced after 14 days, indicating some limited butpotential effect of the adjunctive therapy on the earlystage of periodontal treatment. Significant reduction ofPGF2 and PGE2 in the gingival tissue levels wasobserved in the first 10 days after mechanical therapycombined with NSAID adjunctive treatment (2). Thesefindings suggest that the antiinflammatory effect andsubsequent PD reduction is more evident in the earlyphase of the adjunctive therapy (8).

Overall, no significant differences were observedin PD reduction but in deep periodontal pockets (PD 7mm). This can probably be explained by the fact thatlocalized site measurements produce mean values thatdo not adequately represent the periodontal disease ofthe entire mouth. The larger number of healthy sitesobscures a few deeper sites, commonly found in chronicperiodontitis, since the limited amount of deep pocketsmight not influence the general result. Multi-level dataanalysis considering inter-dependent variables are help-ful but require advanced resources (10).

In addition, the demonstration of additional ben-efits of any adjunctive therapy for periodontitis treat-ment needs adequate study designs. Clinical improve-ment is usually obtained due to a successful mechanicaltherapy and thus, only a small effect can be attributed tothe adjunctive therapy. The lack of difference in PIreduction between groups, after 14 and 28 days, and theclinical improvement in the control group support theidea that most of the clinical benefits frequently comefrom conventional therapy associated to an effectiveplaque control. Therefore, even under medication, some

Figure 2. Percentage of sites on the different time-points accordingto the probing pocket depth (PD). Panel A = shows the increasingnumber of shallow periodontal pockets (< 4 mm) over 14 and 28days. No statistically significant differences (p>0.05) wereobserved for this PD sites. Panel B = shows that the periodontalpockets 4 < 7 mm presented a reduction tendency over time. InPanel C, there is a significant difference (p<0.05) in the percentageof deep periodontal pocket (7 mm) between groups on day 14.The SRP+Loxoprofen therapy promoted faster reduction in thenumber of the deep periodontal pockets but no difference wasobserved after 28 days.

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degree of inflammation and PD reduction may be relatedto patient motivation and cooperation (11). The out-comes of the present study are supported by investiga-tions using NSAIDs for experimental gingivitis treat-ment (8,12).

Regarding NSAID efficacy period, it has beenshown that the inhibitory effect of PGE2 continues onlyduring drug intake phase and will end after drug therapycessation (13). In this short-term evaluation, PD andBOP presented significant improvement during theobservation period. However, no differences were de-tected between groups on day 28, which indicate thatmechanical therapy alone or combined with Loxoprofencan successfully reduce the inflammation and promotepocket depth reduction. Therefore, the extended use ofNSAIDs as an adjunctive therapy is not essential toreduce gingival inflammation and should be limited tothe active phases of periodontal disease.

The long-term use of NSAIDs has been revisitedby US Food and Drug Administration (FDA). FDAreported that the widely use of a high-selective COX-2inhibitor for more than 18 months induces risk of heartattack and stroke (14). This fact may be explained by theeffect of coxibs on the inhibition of endothelial prostacyclin(PGI2) synthesis. PGI2 prevents platelet aggregation andcauses vasodilatation. These effects contrast with plateletCOX-1-derived thromboxane A2 (TxA2), which causesplatelet aggregation, vasoconstriction and vascular pro-liferation. Thus, selective COX-2 blockade favors TxA2and potentially pre-disposes patient to hypertension,heart attack and stroke (15).

One limitation of this study is the lack of bio-chemical analyses of the gingival crevicular fluid (GCF)and tissue biopsy. Nevertheless, although PGs levels ofthe patients were not measured in this experiment, itseems like the present findings are related to the mecha-nism of the COX-2 inhibition and are supported byprevious studies (7-9,12,16).

The effects of NSAIDs on PGE2 levels (2,13),gingival inflammation (17) and alveolar bone loss(16,18,19) have been widely examined in human, animaland in vitro experiments (6,20). In general, the resultshave shown beneficial effect the early phase of peri-odontal treatment, gingivitis and prevention of boneloss. However, the variety of the results found in theliterature can be attributed to differences in the studydesigns, dosage and duration of NSAID therapy, and theselectivity of NSAID to COX-2 (1).

The NSAID used in this study (Loxoprofen) ismore selective to COX-2 than COX-1 and demonstrateda limited advantage when compared to placebo, com-bined or not to the mechanic therapy. However, theclinical significance may be questioned and the indica-tion of this medicament should be restricted to clinicalsituations where deep pockets are present. Conse-quently, the prescription of Loxoprofen as an adjunctfor the non-surgical mechanical therapy may have anindication on the early stages of the treatment ofadvanced forms of periodontal diseases. Further inves-tigations in selected patients may elucidate this potentialindication.

The following conclusions can be drawn: 1.adjunctive antiinflammatory therapy may lead to a fasterand greater probing pocket depth reduction than con-ventional periodontal therapy; 2. health condition shouldbe carefully evaluated before recommending Loxoprofenas an adjunct for clinical use; 3. Loxoprofen antiinflam-matory drug presents potential effect as an adjunct ofperiodontal disease treatment, but long-term clinicaltrials are necessary to confirm its efficacy.

RESUMO

Estratégias terapêuticas adjuvantes que modulam os mediadoresinflamatórios podem ter função significante na terapia periodon-tal. Neste estudo duplo-cego controlado com placebo, 60indivíduos diagnosticados com periodontite foram avaliados por28 dias após tratamento periodontal combinado com inibidorseletivo de COX-2. O grupo experimental foi tratado comraspagem e alisamento radicular combinado com medicação anti-inflamatória Loxoprofeno (RAR+Loxoprofen). O grupo controlefoi tratado com raspagem e alisamento radicular combinado commedicação placebo (Raspagem e alisamento radicular -RAR+placebo). Presença de placa (PI), profundidade de sondagem(PS) e sangramento à sondagem (SS) foram monitoradas comauxílio de uma sonda computadorizada no início do estudo e após14 e 28 dias. Os dois grupos demonstraram melhora clínica emrelação a PS, PI e SS. Também foi observado valores semelhantes(p>0,05) de redução da PS nos períodos de 14 dias (0,4 mm) e 28dias (0,6 mm). No início do estudo, alguns sítios profundos (7mm) do grupo RAR+Loxoprofen foram os responsáveis pelamaior redução da PS depois de 14 dias (p<0,05). A porcentagemde bolsas periodontais profundas 7 mm após 14 dias no grupoRAR+Loxoprofen foi significativamente inferior do que o grupoRAR+placebo (p<0.05). A medicação Loxoprofen apresentapotencial efeito adjuvante à terapia periodontal, mas estudos delongo prazo são necessários para confirmar sua eficácia.

ACKNOWLEDGMENTS

Authors thank support from CAPES, FAPESP (grant # 2001/

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14066-6) and Sankyo Pharma Ltda., Barueri, SP, Brazil. The“first-last-author-emphasis” norm (FLAE) was used for theauthors sequence.

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2 . Vardar S, Baylas H, Huseyinov A. Effects of selectivecyclooxygenase-2 inhibition on gingival tissue levels of pros-taglandin E2 and prostaglandin F2alpha and clinical param-eters of chronic periodontitis. J Periodontol 2003;74:57-63.

3 . Reynolds MA, Prudêncio A, Aichelmann-Reidy ME, Wood-ward K, Uhrich KE. Non-steroidal antiinflammatory drug(NSAID)-derived poly(anhydride-esters) in bone and peri-odontal regeneration. Curr Drug Deliv 2007;4:233-239.

4 . de Queiroz AC, Taba M Jr, O'Connell PA, da Nóbrega PB,Costa PP, Kawata VK et al.. Inflammation markers in healthyand periodontitis patients: a preliminary data screening. BrazDent J 2008;19:3-8.

5 . Kirkwood KL, Cirelli JA, Rogers JE, Giannobile WV. Novelhost response therapeutic approaches to treat periodontaldiseases. Periodontol 2000 2007;43:294-315.

6 . Tipton DA, Flynn JC, Stein SH, Dabbous M. Cyclooxygenase-2 inhibitors decrease interleukin-1beta-stimulated prostag-landin E2 and IL-6 production by human gingival fibroblasts.J Periodontol 2003;74:1754-1763.

7 . Offenbacher S, Williams RC, Jeffcoat MK, Howell TH, OdleBM, Smith MA. et al.. Effects of NSAIDs on beagle crevicularcyclooxygenase metabolites and periodontal bone loss. J Peri-odontal Res 1992;27:207-213.

8 . Taiyeb Ali TB, Waite IM. The effect of systemic ibuprofenon gingival inflammation in humans. J Clin Periodontol1993;20:723-728.

9 . Jeffcoat MK, Reddy MS, Haigh S, Buchanan W, Doyle MJ,Meredith MP. A comparison of topical ketorolac, systemicflurbiprofen, and placebo for the inhibition of bone loss inadult periodontitis. J Periodontol 1995;66:329-338.

10. D’Aiuto F, Ready D, Parkar M, Tonetti MS. Relative contri-bution of patient-, tooth-, and site-associated variability onthe clinical outcomes of subgingival debridement. I. Probingdepths. J Periodontol 2005;76:398-405.

11. Haffajee AD, Thompson M, Torresyap G, Guerrero D,Socransky SS. Efficacy of manual and powered toothbrushes(I). Effect on clinical parameters. J Clin Periodontol2001;28:937-946.

12. Heasman PA, Seymour RA, Kelly PJ. The effect of systemi-cally-administered flurbiprofen as an adjunct to toothbrushingon the resolution of experimental gingivitis. J ClinPeriodontol 1994;21:166-170.

13. Paquette DW, Lawrence HP, McCombs GB, Wilder R, BinderTA, Troullos E. et al.. Pharmacodynamic effects ofketoprofen on crevicular fluid prostanoids in adult periodon-titis. J Clin Periodontol 2000;27:558-566.

14. Kuehn BM. FDA panel: keep COX-2 drugs on market: blackbox for COX-2 labels, caution urged for all NSAIDs. Jama2005;293:1571-1572.

15. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R,Finn P. et al.. Cardiovascular risk associated with celecoxib ina clinical trial for colorectal adenoma prevention. N Engl JMed 2005;352:1071-1080.

16. Offenbacher S, Odle BM, Braswell LD, Johnson HG, Hall CM,McClure H. et al.. Changes in cyclooxygenase metabolites inexperimental periodontitis in Macaca mulatta. J PeriodontalRes 1989;24:63-74.

17. Heasman PA, Seymour RA, Boston PF. The effect of atopical non-steroidal antiinflammatory drug on the develop-ment of experimental gingivitis in man. J Clin Periodontol1989;16:353-358.

18. Williams RC, Jeffcoat MK, Howell TH, Rolla A, Stubbs D,Teoh KW. et al.. Altering the progression of human alveolarbone loss with the non-steroidal antiinflammatory drugflurbiprofen. J Periodontol 1989;60:485-490.

19. Holzhausen MC, Rossa Junior E, Marcantonio Junior PO,Nassar DM, Spolidorio LC. Effect of selectivecyclooxygenase-2 inhibition on the development of ligature-induced periodontitis in rats. J Periodontol 2002;73:1030-1036.

20. Vardar S, Buduneli E, Baylas H, Berdeli AH, Buduneli N, AtillaG. Individual and combined effects of selectivecyclooxygenase-2 inhibitor and omega-3 fatty acid on endot-oxin-induced periodontitis in rats. J Periodontol 2005;76:99-106.

Acepted March 13, 2008

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Braz J Med Biol Res 40(1) 2007

Etoricoxib in experimental periodontitisBrazilian Journal of Medical and Biological Research (2007) 40: 117-125ISSN 0100-879X

Comparison of etoricoxib andindomethacin for the treatment ofexperimental periodontitis in rats

1Departamento de Fisiologia e Farmacologia,2Departamento de Morfologia, Faculdade de Medicina,Universidade Federal do Ceará, Fortaleza, CE, Brasil

M.C.F. Azoubel1,A.M.A. Menezes1,

D. Bezerra1, R.B. Oriá2,R.A. Ribeiro1

and G.A.C. Brito2

Abstract

We investigated the effect of etoricoxib, a selective cyclooxygenase-2 inhibitor, and indomethacin, a non-selective cyclooxygenase inhib-itor, on experimental periodontitis, and compared their gastrointesti-nal side effects. A ligature was placed around the second upper leftmolars of female Wistar rats (160 to 200 g). Animals (6 per group)were treated daily with oral doses of 3 or 9 mg/kg etoricoxib, 5 mg/kgindomethacin, or 0.2 mL saline, starting 5 days after the induction ofperiodontitis, when bone resorption was detected, until the sacrificeon the 11th day. The weight and survival rate were monitored.Alveolar bone loss (ABL) was measured as the sum of distancesbetween the cusp tips and the alveolar bone. The gastric mucosa wasexamined macroscopically and the periodontium and gastric andintestinal mucosa were examined by histopathology. The ongoingABL was significantly inhibited (P < 0.05) by 3 and 9 mg/kg etoricoxiband by indomethacin: control = 4.08 ± 0.47 mm; etoricoxib (3 mg/kg)= 1.89 ± 0.26 mm; etoricoxib (9 mg/kg) = 1.02 ± 0.14 mm; indometh-acin = 0.64 ± 0.15 mm. Histopathology of periodontium showed thatetoricoxib and indomethacin reduced inflammatory cell infiltration,ABL, and cementum and collagen fiber destruction. Macroscopic andhistopathological analysis of gastric and intestinal mucosa demon-strated that etoricoxib induces less damage than indomethacin. Ani-mals that received indomethacin presented weight loss starting on the7th day, and higher mortality rate (58.3%) compared to etoricoxib(0%). Treatment with etoricoxib, even starting when ABL is detected,reduces inflammation and cementum and bone resorption, with fewergastrointestinal side effects.

CorrespondenceG.A.C. Brito

Departamento de Fisiologia

e Farmacologia

Faculdade de Medicina, UFC

Rua Coronel Nunes de Melo, 1127

60430-270 Fortaleza, CE

Brasil

Fax: +55-85-3366-8333

E-mail: gerlybrito@hotmail.com

Research supported by CNPq and

Fundação Cearense de Pesquisa e

Cultura (FUNCAP).

Received April 17, 2006

Accepted October 27, 2006

Key words• Alveolar bone loss• Inflammation• Periodontitis• Cyclooxygenase inhibitors• Etoricoxib• Indomethacin

Introduction

Periodontitis is a chronic inflammatorydisease characterized by destruction of thetooth-supporting connective tissue and ce-mentum, bone resorption, leukocyte infiltra-tion, and periodontal pocket formation (1,2).

Although bacteria are considered to be theprimary etiologic agents of periodontal dis-ease (3,4), the pathogenesis of periodontitisinvolves host-bacterial interaction followedby release of inflammatory mediators suchas eicosanoids and cytokines (5). Arachi-donic acid metabolites, mainly prostaglan-

262 JADA 142(3) http://jada.ada.org March 2011

S T O R YC O V E R

Inflammation increas-ingly is recognized as aclinically significantfactor in the initiation,

progression and ultimateinstability of atheroscle-rotic plaques in patientswith coronary artery dis-ease (CAD).1,2 In thisregard, chronic periodon-titis is a common chronicinflammatory disease thatincreasingly is being recog-nized as having an associa-tion with, and potentialcausal relationship to,CAD.3,4 Therapeutic strate-gies that resolve inflamma-tion associated with both ofthese diseases and thataffect CAD’s onset and pro-gression are needed. Theinvestigators in theWomen’s Health Initiativeclinical trial did not find afavorable risk-benefit pro-file for hormone replace-ment therapy in the pri-mary prevention of CAD.5

Because CAD is a leadingcause of death in postmen -opausal women,6 noveltherapies to reduce sys-temic inflammation shouldDr. Payne is the associate dean for research, a professor, and the F. Gene and Rosemary Dixon Endowed Chair in Dentistry, Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Lincoln, Neb. 68583-0740, e-mail “jbpayne@unmc.edu”. Address reprint requests to Dr. Payne.Dr. Golub is a SUNY Distinguished Professor, Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, N.Y.Dr. Stoner is an associate professor and chair, Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City.Dr. Lee is a research assistant professor, Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, N.Y.Dr. Reinhardt is the BJ and Ann Moran Professor of Periodontology, Department of Surgical Specialties, College of Dentistry, University of Nebraska MedicalCenter, Lincoln.Dr. Sorsa is a professor and chairman, Department of Cell Biology of Oral Diseases, Institute of Dentistry, University of Helsinki; and chief dentist, Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital.Dr. Slepian is professor of medicine (cardiology) and biomedical engineering, Sarver Heart Center, and McGuire Scholar, Eller College of Management, University of Arizona, Tucson.

The effect of subantimicrobial-dose–doxycycline periodontal therapy on serumbiomarkers of systemic inflammationA randomized, double-masked, placebo-controlled clinical trialJeffrey B. Payne, DDS, MDentSc; Lorne M. Golub, DMD, MSc; Julie A. Stoner, PhD; Hsi-mingLee, PhD; Richard A. Reinhardt, DDS, PhD; Timo Sorsa, DDS, PhD; Marvin J. Slepian, MD

AB ST RACTBackground. Periodontitis has been reported to be associ-ated with coronary artery disease (CAD). Research is needed todetermine if therapies that improve periodontal health alsoreduce systemic measures of inflammation associated with bothdiseases. Methods. The study registrar randomly assigned 128 eligible postmenopausalwomen with chronic periodontitis to a twice-daily regimen of subantimicrobial-dose–doxycycline (SDD) or placebo tablets for two years as an adjunct to perio -dontal maintenance therapy. Through a supplement to the main trial, in whichthey investigated alveolar bone and clinical attachment level changes, theauthors assayed inflammatory mediators and lipid profiles in baseline, one-yearand two-year serum samples. The authors analyzed the data by using general-ized estimating equations. Results. In the intent-to-treat analysis across two years, SDD treatmentreduced median high-sensitivity C-reactive protein (hs-CRP) by 18 percent (pri-mary outcome; P = .02) and reduced serum matrix metalloproteinase (MMP)-9(92 kilodalton gelatinase; difference in mean scanning units, −28.44; P < .001),with no significant effect on serum lipids. However, in women more than fiveyears postmenopausal, SDD elevated the level of high-density lipoprotein (HDL)cholesterol (difference in means [milligrams per deciliter], 5.99; P = .01). Conclusion. A two-year SDD regimen in postmenopausal women significantlyreduced the serum inflammatory biomarkers hs-CRP and MMP-9 and, amongwomen more than five years postmenopausal, increased the HDL cholesterollevel. Clinical Implications. SDD significantly reduced the systemic inflammatorybiomarkers hs-CRP and MMP-9. More research is needed to determine whetherSDD has a role in managing the care of patients at risk of developing CAD.Key Words. C-reactive protein; doxycycline; inflammation; high-densitylipoprotein cholesterol; matrix metalloproteinases; periodontitis; serum inflam-matory biomarkers.JADA 2011;142(3):262-273. ClinicalTrials.gov identifier NCT00066027.

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tory of diabetes, or hadosteoporosis at eitherthe lumbar spine or thefemoral neck.

Serum inflamma-tory mediatoranalyses. We analyzedspecimen samples inthree batches. We ana-lyzed all samples froman individual patient inthe same batch, andtreatment assignmentswere masked and bal-anced among thebatches by means of theblock-randomizeddesign.

hs-CRP. Researchassistants trained inphlebotomy drew non-fasting blood samples atbaseline, one-year andtwo-year appointments.We obtained serum byusing standard tech-nique and stored it at −80˚C until analysis. Wemeasured hs-CRP—the primary outcomemeasure in this supplemental trial—by using ahigh-sensitivity enzyme-linked immunosorbentassay (ELISA) (MP Biomedicals, DiagnosticDivision, Orangeburg, N.Y.). The assay had asensitivity of 0.1 mg per liter.

Cytokine. We used ELISA (Biosource,Camarillo, Calif.) to measure interleukin (IL)-6,IL-1β and tumor necrosis factor (TNF)-α levels.The sensitivities to detect IL-6, IL-1β and TNF-α were as low as 2, 1 and 1.7 picograms per mil-liliter, respectively.

Myeloperoxidase. We used ELISA (HycultBiotech, Uden, Netherlands) to measuremyeloperoxidase levels. The sensitivity to detectmyeloperoxidase was as low as 0.4 nanogramsper mL.

Lipid profile. Staff of the Stony Brook Uni-versity clinical chemistry laboratory measuredtotal cholesterol, high-density lipoprotein (HDL)cholesterol and triglyceride levels by using stan-dard techniques and reagents with the Roche/Hitachi Modular Analytics Systems (RocheDiagnostics, Indianapolis). Levels of low-densitylipoprotein (LDL) cholesterol and very low-den-sity lipoprotein (VLDL) cholesterol were basedon results calculated as follows: LDL choles-terol, total cholesterol – (HDL cholesterol +triglycerides ÷ 5); VLDL cholesterol, triglyc-

erides ÷ 5. The sensitivities to detect lipids wereassay ranges of 3 to 800 mg per deciliter fortotal cholesterol, 3 to 120 mg/dL for HDL choles-terol and 4 to 1,000 mg/dL for triglycerides.

MMP-2 and MMP-9. We measured MMP-2and MMP-9 levels by means of gelatin zymog-raphy, as described previously,17 and we presentthe data as densitometric units.

MMP-8 and tissue inhibitor of metallo-proteinases (TIMP)-1. We determined serumMMP-8 concentration by using time-resolvedimmunofluorometric assay22 and determinedTIMP-1 by using Western blot plus densito-metric computerized quantitation, as previouslydescribed.23 The detection limit for the MMP-8assay was 0.08 ng/mL.

Statistical analyses. We justified the sup-plemental study sample size on the basis of hs-CRP data presented by Brown and colleagues.17

We estimated the average two-year change inhs-CRP to be a decrease of 2.5 mg/L for partici-pants in the SDD group and a decrease of 0.5mg/L for participants in the placebo group, witha standard deviation (SD) of 3.0 mg/L. A totalsample of 50 participants per group resulted in90 percent power to detect a true difference of 2mg/L in the mean change in hs-CRP across thetwo-year period, assuming an SD of 3.0 mg/Land a two-sided .05 α level. We performed

TABLE 2

Participants’ baseline medication use.MEDICATION NO. (%) OF PARTICIPANTS

USING MEDICATIONP VALUE

Placebo Group(n = 62)

SDD* Group(n = 51)

Aspirin (Any Dose) 9 (15) 9 (18) .8

Nonsteroidal Anti-InflammatoryAgents

0 0 Not applicable

Steroids 0 0 Not applicable

Antibiotic Agents 1 (2) 0 > .9

Statins 6 (10) 8 (16) .4

Nonstatin Lipid-Lowering Agents 0 0 Not applicable

Diuretics 8 (13) 4 (8) .5

β Blockers 3 (5) 3 (6) > .9

Calcium Channel Blockers 4 (6) 1 (2) .4

Angiotensin-Converting EnzymeInhibitors/Angiotensin ReceptorBlockers

6 (10) 6 (12) .8

Nitrates 0 0 Not applicable

Thienopyridine AdenosineDiphosphate Receptor Antagonists

0 0 Not applicable

* SDD: Subantimicrobial-dose doxycycline.

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(a secondary endpoint), treatment with SDD asan adjunct to periodontal maintenance signifi-cantly decreased the odds of more progressiveperiodontitis by 19 percent relative to placeboplus adjunctive periodontal maintenance,according to the results of intent-to-treatanalyses (odds ratio = 0.81; 95 percent CI, 0.67to 0.97; P = .03).19 Moreover, adverse event expe-riences were similar between the SDD andplacebo groups, and there was no evidence ofmicrobiological resistance in the SDD group rel-ative to the placebo group.18,21 SDD representsan attractive adjunctive pharmacological meansof reducing systemic inflammatory biomarkers:it is relatively inexpensive, being availablegenerically, and repeatedly has been demon-strated to be safe.18,21,33 The FDA approved SDDin 1998 as a safe and effective adjunct to scalingand root planing in the treatment of chronicperiodontitis (for the findings of the clinical trialthat led to the FDA approval, see Caton and colleagues33).

Limitations of our study include the loss ofseveral participants to follow-up, because someof them withdrew before initiation of thisaddendum study. However, participants whosefollow-up was incomplete did not differ fromthose whose follow-up was complete in terms ofbaseline characteristics. Also, given the multiplehypothesis tests that we performed, one mustinterpret subgroup effects cautiously. Finally,inference is limited to the target population:postmenopausal women with chronic periodon-titis and osteopenia who have no history ofmyocardial infarction, angina or stroke. Extrap-olation to the general population of postmeno -pausal women at risk of experiencing cardiovas-cular disease requires further study.

The postmenopausal women in our studywere in good general health, although all hadchronic periodontitis, which generates elevatedlevels of proinflammatory cytokines such as IL-1β,34 TNF-α,34 IL-635 and tissue-destructiveMMPs (such as MMP-8 and MMP-9)36,37 in theperiodontium. These aforementioned cytokines,particularly IL-6, are carried by the circulationto the liver, where they induce expression ofacute-phase proteins, notably CRP.38 In supportof this pathway linking periodontitis and CADrisk, investigators have reported that patientswith self-reported periodontitis show elevationsin serum biomarkers (for instance, hs-CRP andbiomarkers of endothelial dysfunction and dys-lipidemia) associated with increased risk ofdeveloping CAD.39 Although investigatorsrecently have questioned a causal associationbetween CRP and CAD,40 inflammation is recog-

nized as playing a key role in CAD pathogen-esis, and chronic inflammatory periodontitis cancontribute to the systemic inflammatoryburden. Furthermore, evidence indicates thattetracyclines, by means of nonantimicrobialmechanisms, can be effective in treating bothpathogenic periodontitis and CAD path-ways.11,41,42 However, a large multicenter clinicaltrial of longer duration will be necessary todetermine whether SDD can reduce risk of CADdevelopment in addition to reducing serum bio-markers of systemic inflammation.

CONCLUSIONSIn postmenopausal women who are in good gen-eral health but who have chronic periodontitisand systemic osteopenia, SDD—an approvedtreatment for chronic periodontitis—reducedserum hs-CRP and MMP-9, and, in subgroups,increased HDL cholesterol, reduced MMP-2 andreduced the MMP-8:TIMP-1 ratio. Because SDDhas a favorable safety profile and is relativelyinexpensive, SDD is a potentially attractivepharmaceutical approach to managing chronicsystemic inflammation. ■

Disclosures. Dr. Golub is listed as an inventor on patents on thetest medication in this clinical trial, and those patents have beenassigned fully to his institution, Stony Brook University, State Uni-versity of New York. He is also a consultant to Galderma Researchand Development, Lausanne, Switzerland, which has licensed aseries of tetracycline patents from Stony Brook University, StateUniversity of New York. None of the other authors reported any disclosures.

Subantimicrobial-dose–doxycycline and placebo tablets were pro-vided by CollaGenex Pharmaceuticals, Newtown, Pa.

The project was supported by grant R01DE012872 from the National Institute of Dental and Craniofacial Research to Dr. Jeffrey B. Payne, principal investigator, and Dr. Lorne M. Golub,co-principal investigator. The content is solely the responsibility ofthe authors and does not necessarily represent the official views ofthe National Institute of Dental and Craniofacial Research or theNational Institutes of Health. Dr. Sorsa was supported by grantsfrom the Academy of Finland and the Helsinki University CentralHospital Research Foundation.

1. Libby P. Inflammation in atherosclerosis. Nature 2002;420(6917):868-874.

2. Montecucco F, Mach F. Common inflammatory mediators orches-trate pathophysiological processes in rheumatoid arthritis and ather-osclerosis. Rheumatology (Oxford) 2009;48(1):11-22.

3. Craig RG, Yip JK, So MK, Boylan RJ, Socransky SS, HaffajeeAD. Relationship of destructive periodontal disease to the acute-phase response. J Periodontol 2003;74(7):1007-1016.

4. Friedewald VE, Kornman KS, Beck JD, et al.; American Journalof Cardiology; Journal of Periodontology. The American Journal ofCardiology and Journal of Periodontology Editors’ Consensus: peri-odontitis and atherosclerotic cardiovascular disease. Am J Cardiol2009;104(1):59-68.

5. Rossouw JE, Anderson GL, Prentice RL, et al.; Writing Group forthe Women’s Health Initiative Investigators. Risks and benefits ofestrogen plus progestin in healthy postmenopausal women: principalresults from the Women’s Health Initiative randomized controlledtrial. JAMA 2002;288(3):321-333.

6. Rees M, Stevenson J; British Menopause Society Council. Pri-mary prevention of coronary heart disease in women. Menopause Int2008;14(1):40-45.

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Indian Journal of Dental Research

ORIGINAL RESEARCH

Year : 2010 | Volume : 21 | Issue : 3 | Page : 326-329

Evaluation of the C-reactive protein serum levels in periodontitis patients with or without atherosclerosis

Kaustubh S Thakare, Vikas Deo, Manohar L BhongadeDepartment of Periodontics and Implantology, Sharad Pawar Dental College, Deemed University, Sawangi (Meghe), Wardha - 442 001, Maharashtra, India

Date of Submission 19-Jun-2009

Date of Decision 05-Sep-2009

Date of Acceptance 01-Oct-2009

Date of Web Publication

29-Sep-2010

Abstract

Background: Several studies suggested an association between periodontal disease and cardiovascular disease (CVD). C- reactive protein is elevated in periodontitis patients and has been found to be a predictor of increased risk for cardiovascular disease. Since, CRP is known to play a role in pathogenesis of atherosclerosis, the present study was undertaken to evaluate the serum levels of CRP in periodontitis patients with or without atherosclerosis. Materials and Methods : A total of 45 patients, 15 chronic periodontitis patients with atherosclerosis (Group A), 15 chronic periodontitis patients with no history of any systemic disease (Group B), and 15 clinically healthy individuals with no history of periodontal or systemic disease (Group C) within age range of 30 to 55 years were selected for the study. PI, PBI, PPD, CAL and radiographic marginal alveolar bone level were assessed in all the three groups. CRP levels were assessed with 'Turbi-latex' kit using turbidimetric analysis.Results : The mean CAL recorded was 4.9mm in group A, 4.6mm in group B and 1.9 mm in group C. The mean radiographic marginal bone level was 45 to 50% in group A, 45 to 50% in group B and 90 to 95% in group C. Mean serum C-reactive protein level was significantly higher in group A (8.9 mg/l), as

Fifteen chronic periodontitis patients with angiographically proven atherosclerosis in the age group of 30 - 55 years (mean age 44.56±0.11years) were selected from the general medicine ward of A. V. B. R. Hospital, Wardha. Atherosclerosis was defined as the intima media wall thickening > 1.2mm in carotid arteries and presence of calcified plaque in coronary and carotid arteries. There were 30 systemically healthy age matched patients; 15 of them with moderate to severe chronic periodontitis and 15 periodontally healthy patients (controls) were selected from department of periodontics, S. P. D. College, Wardha. Chronic periodontitis patients showed radiographic evidence of marginal alveolar bone loss ≥ 30%, affecting at least 50% of dentition and clinical attachment loss ≥ 4mm at a minimum of six sites. The following patients were excluded from the study:

Patients with a history of diabetes

History and/or presence of any other systemic infection.

Treatment with any medication known to affect the serum level of inflammatory markers (e.g. non-steroidal anti-inflammatory drugs)

Patients on any medication that could affect the manifestation of periodontal disease, such as chronic antibiotic use, phenytoin, cyclosporine, anti-inflammatory drugs, calcium channel blockers or corticosteroids

Smokers or users of any tobacco products

Patients treated by periodontal therapy in past six months

Pregnant females or lactating mothers

Prior to initiation, the purpose and design of study was explained to patients and an informed consent form was signed by every patient. Study protocol was approved by research and ethical committee of D.M.I.M.S, Wardha. The present study was a randomized, parallel design with a total of 45 patients in the age group of 30-55 years distributed into three groups. The first group included healthy individuals (controls, group A), second group included patients with chronic periodontitis only (group B), and third group included patients with chronic periodontitis and atherosclerosis (group C).

Periodontal disease status was determined using clinical and radiographic criteria. Clinical evaluation was based on full mouth plaque index (PI), [12] papillary bleeding index (PBI), [13] probing pocket depth (PPD) at six sites per tooth and clinical attachment level (CAL) at four sites per tooth. Radiographic alveolar bone level was assessed using standard orthopantomograph (O.P.G.).

If the presence of the alveolar bone from cementoenamel junction to root apex can be considered as about 100% alveolar bone present, alveolar bone level was quantified according to the existing alveolar bone level up to the root apex on the O.P.G. For example, if the alveolar bone level was at the level near coronal two-third, the existing bone level was considered to be 65-70 %. Similarly, if the alveolar bone level was near the mid-root region, the existing bone level was considered to be 50-55 %. Average alveolar bone level for each group was calculated by summation of alveolar bone level in each patient in the group divided by the total number of patients in the group.

Table 2 :Comparison of clinical parameters, radiographic bone level and serum CRP levels between different groups (Mean±SD)

Click here to view

Group C (chronic periodontitis and atherosclerosis [CP+ATH]) showed mean PI score of 2.42±0.27, mean PBI score of 2.37±0.25, mean PPD 5.30±0.71 mm, mean CAL 5.67±0.79 mm, mean radiographic marginal bone level 35 - 40% (39.16±5.56) and mean serum CRP levels 8.02±1.23 mg/L [Table 2]. The mean PI, PBI, PPD, CAL, radiographic marginal bone levels and serum CRP were compared between group A and group C using student's unpaired t - test. There were statistically significant differences in PI (1.50±0.07), PBI (1.50±0.07), PPD (3.53±0.18), CAL (3.90±0.20), radiographic marginal bone level (-50.50±1.57) and serum CRP levels (7.07±0.32) [Table 2].

Results showed significant and positive correlations among all clinical parameters, radiographic marginal bone level and serum CRP levels.

Discussion

Several cross sectional and longitudinal epidemiological studies are consistent in reporting that periodontitis patients are at higher risk for cardiovascular diseases including coronary artery diseases and stroke. The association is hypothesized to be linked to direct effects of periodontal pathogens or indirect host mediated effects triggered by infection. [14],[15] Systemic inflammatory host responses in periodontitis are suggested to be one of the possible underlying mechanisms of this relationship. [15] CRP and other acute phase molecules possess a wide variety of functions, including pro-inflammatory properties, activation of complement factors, neutralization of invasive pathogens, stimulation of repair, and regeneration of a variety of tissues. CRP represents an emerging and reliable marker of acute phase response to infectious burdens and/or inflammation. [16]

Several recent studies have emphasized that even moderately elevated CRP serum levels are predictors of increased risk of cardiovascular disease among apparently healthy individuals. [17] Chronic bacterial infections such as periodontitis are one of the established risk factors for moderately elevated CRP. [18] Previous studies [19],[20]

have demonstrated that CRP levels are higher in periodontitis patients than in periodontally healthy subjects and that serum CRP levels are higher in patients with more severe periodontitis.

7. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontol 1996;67:1123-37.

8. Chiu B. Multiple infections in carotid atherosclerotic plaques. Am Heart J 1999;138:S534-6.

9. Loos BG. Systemic markers and inflammation in Periodontics.J Periodontol 2005;76:2106-15.

10. D'Aiuto F, Ready D, Tonetti MS. Periodontal disease and C- reactive protein associated cardiovascular risk. J Periodontal Res 2004:39;236-41.

11. Beck JD, Elter JR, Heiss G, Couper D, Mauriello SM, Offenbacher S. Relationship of Periodontal disease to carotid artery intima media wall thickness: The atherosclerotic risk in communities (ARIC) study. Arterioscler Thromb Vasc Biol 2001;21;1816-22.

12. Mόhlemann HR. Psychological and chemical mediators of gingival health. J Prev Dent 1977;4:6-17.

13. Turesky S, Gilmore ND, Glickman I. Reduced plaque formation by the chloromethyl analogue of vitamin C. J Periodontol 1970;41:41-9.

14. Rose LF, Genco RJ, Cohen DW, Mealy BL. Periodontal medicine. Hamilton, Ontario BC: Deckeer Inc. Z; p. 73-8.

15. Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos CT. Examination of relation between periodontal health status and cardiovascular risk factors: Total and high density lipoprotein, cholesterol, C-reactive protein and plasma fibrinogen. Am J Epidemiol 2000;151;273-82.

16. Ioannidou E, Malekzadeh T, Dongari-Bagtzoglou A. Effect of periodontal treatment on serum C-reactive protein levels: A systematic review and meta analysis. J Periodontol 2006;77:1635-42.

17. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin and risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336;973-9.

18. lade GD, Offenbacher S, Beck JD, Heiss G, Pankow JS. Acute phase response to periodontal disease in the US population. J Dent Res 2000;79;49-57.

19. Ebersole JL, Machen RL, Steffen MJ, Willmann DE. Systemic acute phase reactants. C reactive protein and hepatoglobin in adult periodontitis. Clin Exp Immunol 1997;107;347-52.

20. Saito T, Murakami M, Shimazaki Y, Oobayashi K, Matsumoto S, Koga T. Association between alveolar bone loss and elevated serum C- reactive protein in Japanese men. J Periodontol 2003;74:1741-6.

21. Salzberg TN, Overstreet BT, Rogers JD, Califano JV, Best AM, Schenkein HA. C- reactive protein levels in patients with aggressive periodontitis. J Periodontol 2006;77:933-9.

22. Fredriksson MI, Figueredo CM, Gustafsson A, Bergstrφm KG, Asman BE. Effect of periodontitis

ARCOXIA Tablet DS A120410 v4 (MK0663-NZL-2012-004352) Page 1

NEW ZEALAND DATA SHEET ARCOXIA® (etoricoxib, MSD) 30mg, 60mg, 90mg & 120mg tablets PRESENTATIONS 30mg tablet: A blue green apple shaped biconvex film coated tablet debossed 101 on one side and ACX 30 on the other. Dimensions are 5.69 mm x 5.54 mm. 60mg tablet: A dark green apple shaped biconvex film coated tablet debossed 200 on one side and ARCOXIA 60 on the other. Dimensions are 7.16 mm x 6.99 mm. 90mg tablet: A white apple shaped biconvex film coated tablet debossed 202 on one side and ARCOXIA 90 on the other. Dimensions are 8.20 mm x 8.00 mm. 120mg tablet: A pale green apple shaped biconvex film coated tablet debossed 204 on one side and ARCOXIA 120 on the other. Dimensions are 9.03 mm x 8.80 mm. Do not halve tablet. Studies on divided tablets have not been performed. THERAPEUTIC CLASS ARCOXIA (etoricoxib) is a member of a class of arthritis/analgesia medications called Coxibs. ARCOXIA is a highly selective inhibitor of cyclooxygenase-2 (COX-2). INDICATIONS ARCOXIA is indicated for: • Acute and chronic treatment of the signs and symptoms of osteoarthritis (OA) and

rheumatoid arthritis (RA) • The management of ankylosing spondylitis (AS) • Treatment of acute gouty arthritis • Relief of acute pain • Relief of chronic musculoskeletal pain The decision to prescribe a selective COX-2 inhibitor should only be made: • if non-pharmacological interventions and simple analgesic therapy have been tried and

found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient; and

• after assessment of the individual patient's overall risk factors for developing severe adverse events e.g. history of cardiovascular, renal, or gastrointestinal disease (see Contraindications and Warnings and Precautions).

DOSAGE AND ADMINISTRATION ARCOXIA is administered orally. ARCOXIA may be taken with or without food. Do not halve tablet. Studies on divided tablets have not been performed.

ARCOXIA Tablet DS A120410 v4 (MK0663-NZL-2012-004352) Page 3

CONTRAINDICATIONS ARCOXIA is contraindicated in patients with: • Hypersensitivity to any component of this product. A history of asthma, urticarial or other

allergic reactions after taking aspirin or other NSAIDs. • Congestive heart failure (NYHA II-IV). • Patients with hypertension whose blood pressure is persistently above 140/90 mmHg and

has not been adequately controlled. • Established ischaemic heart disease, peripheral artery disease and/or cerebrovascular

disease (including patients who have recently undergone coronary artery bypass graft surgery or angioplasty).

• Use in the peri-operative period in patients undergoing cardiac or major vascular surgery. • Severe hepatic dysfunction (serum albumin <25 g/L or Child-Pugh score ≥10). • Active peptic ulceration or gastrointestinal bleeding. • An estimated creatinine clearance < 30mL/min. WARNINGS AND PRECAUTIONS

Cardiovascular Effects Clinical trials suggest that the selective COX-2 inhibitor class of medicines (of which etoricoxib is one) may be associated with an increased risk of thrombotic events (especially MI and stroke), relative to placebo and some Non-steroidal Anti-inflammatory Drugs, NSAIDs (naproxen). As the cardiovascular risks of selective COX-2 inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. Patients on long-term treatment should be reviewed regularly, such as every three months, with regards to efficacy, risk factors and ongoing need for treatment. Prescribers should inform the individual patient of the increased risk when prescribing etoricoxib to patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). Two large, controlled clinical trials of a different COX-2 selective inhibitor for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. In the absence of comparable data with etoricoxib, it may be assumed that patients at high risk of cardiovascular disease (including patients with diabetes, hyperlipidaemia, hypertension, or smokers) who are undergoing any major surgery may face an increased risk of developing a cardiovascular event. Patients with significant risk factors for cardiovascular events should only be treated with etoricoxib after careful consideration of the patient’s overall risk and the potential risks and benefits of alternative analgesic therapies. Aspirin Substitution Selective COX-2 inhibitors are not a substitute for aspirin for cardiovascular prophylaxis because of their lack of effect on platelets. Because etoricoxib, a member of this class, does not inhibit platelet aggregation, antiplatelet therapies should not be discontinued. There is no evidence that concurrent use of aspirin decreases the risk of cardiovascular adverse events associated with COX-2 inhibitors, including etoricoxib. Gastrointestinal Effects Physicians should be aware that individual patients may develop upper gastrointestinal (GI) ulcers/ulcer complications irrespective of treatment. Although the risk of GI toxicity is not eliminated with ARCOXIA, the results of the MEDAL Program demonstrate that in patients

http://www.medsafe.govt.nz/profs/adverse/Minutes123.htm

2.2.1 COX-2 Inhibitors and Cardiovascular SafetyJune 2005 minute item 2.1.1; March 2005 minute items 3.1.8.1,2,4,5 and 6

Issue

In March 2005 the Committee recommended that the data sheets and consumer medicine information (CMIs) for celecoxib, etoricoxib, lumiracoxib, parecoxib and meloxicam should be updated (see the minutes of the 121st MARC meeting for details).

Outcome

Following negotiation with the COX-2 inhibitor product sponsors, the required data sheet changes were in the process of being finalised at the time of this meeting. The majority of the required warning statements, or words of the same intent, had been accepted by the sponsors. However, as a result of the negotiations, Medsafe accepted variations to some of the required warning statements, as detailed below:

Statement 1

Medsafe's original request was to add the following to the Indications section of the data sheet: "[Product name] should not be used unless alternative therapies have been used and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient."

Following negotiation an alternative statement was considered by Medsafe to be acceptable: "The decision to prescribe a selective COX-2 inhibitor should only be made:

if non-pharmacological interventions and simple analgesic therapy have been tried and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient; and

after assessment of the individual patient's overall risk factors for developing severe adverse events e.g. history of cardiovascular, renal, or gastrointestinal disease."

Statement 2

Medsafe's original request was to add the following to the Indications section of the data sheet: "[Product name] should be used primarily for the short-term treatment of acute conditions (up to one week). In patients for whom longer-term use may be required, treatment efficacy should bereviewed after two weeks and [product name] withdrawn if there is a lack of therapeutic benefit. Patients on long-term treatment should be reviewed every three months with regards to riskfactors and the ongoing need for treatment."

Following negotiation an alternative statement was considered by Medsafe to be acceptable: "As the cardiovascular risks of the selective COX-2 inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.

Eto Etoricoxib 60 mg, 90 mg & 120 mg tablet

Etoricoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities. It is a potent, orally active, highly selective cyclooxygenase-2 (COX-2) inhibitor within and above the clinical dose range. COX-2 has been shown to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. Selective inhibition of COX-2 by etoricoxib decreases these clinical signs and symptoms with decreased GI toxicity and without effects on platelet function. INDICATIONS It is indicated for pain and inflammation in osteoarthritis, in rheumatoid arthritis, in acute gouty arthritis; in chronic low back pain; in ankylosing spondylitis and in other acute and chronic musculoskeletal disorders; primary dysmenorrhoea and pain following dental surgery. DOSAGE AND ADMINISTRATION Adult and adolescent over 16 years: Eto is administered orally and may be taken with or without food. The onset of drug effect may be faster when Eto is administered without food. This should be considered when rapid symptomatic relief is needed.

• In case of osteoarthritis (can be given for 14 weeks), chronic low back pain and acute & chronic musculoskeletal disorders (can be given for 12 weeks) : 60 mg once daily.

• In case of rheumatoid arthritis (can be given for 12 weeks) and ankylosing spondylitis (can be given for 6 weeks): 90 mg once daily.

• In case of Pain following dental surgery, acute gouty arthritis and primary dysmenorrhoea (can be given for 8 days): 120 mg once daily.

Safety and effectiveness of etoricoxib in paediatric patients have not been established. CONTRAINDICATIONS Patients with the history of hypersensitivity to etoricoxib or to any of the components of it and who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria, or allergic-type reactions after taking acetylsalicylic acid or NSAIDs. USE IN PREGNANCY & LACTATION Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib is contraindicated in pregnancy. If a woman becomes pregnant during treatment, etoricoxib should be discontinued. It is not known whether this drug is excreted in human milk. Mothers who need to take this medicine should not breastfeed.

SIDE EFFECT Common side effects of etoricoxib are headache, muscle cramps, dry mouth, taste disturbance, mouth ulcers, flatulence, constipation, appetite and weight changes, chest pain, fatigue, paraesthesia, influenza-like syndrome, and myalgia. PRECAUTIONS In patients with advanced renal disease, treatment with Eto is not recommended. Clinical experience in patients with estimated creatinine clearance of <30 mL/min is very limited. If therapy with Eto is initiated in such patients, then close monitoring of the patient's renal function is advisable. Caution should be made when initiating treatment with it in patients with considerable dehydration. It is advisable to rehydrate patients prior to starting therapy with it. The possibility of fluid retention, oedema or hypertension should be taken into consideration when it is used in patients with pre-existing oedema, hypertension, or heart failure. Independent of treatment, patients with a prior history of GI perforation, ulcers and bleeding (PUB) and patients more than 65 years of age are known to be at a higher risk for PUB. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for persistently abnormal liver function tests. If persistently abnormal liver function tests (three times the upper limit of normal) are detected, it should be discontinued. It should be used with caution in patients who have previously experienced acute asthmatic attacks, urticaria, or rhinitis, which were precipitated by salicylates or non-selective cyclooxygenase inhibitors. It may mask fever, which is a sign of infection. The physician should be aware of this when using it in patients being treated for infection. OVERDOSE No overdoses of etoricoxib were reported during clinical trials. In clinical studies, administration of single doses of etoricoxib up to 500 mg and multiple doses up to 150 mg/day for 21 days did not result in significant toxicity. WARNING Keep out of the reach of children. PACKAGING Eto 60 : Box containing 5x10 tablets in blister pack. Each film-coated tablet contains etoricoxib INN 60 mg. Eto 90 : Box containing 3x10 tablets in blister pack. Each film-coated tablet contains etoricoxib INN 90 mg. Eto 120 : Box containing 2x10 tablets in blister pack. Each film-coated tablet contains etoricoxib INN 120 mg. PHARMACEUTICAL PRECAUTIONS keep in a dry place away from light and heat.