Periostat® in the News

Periostat^® in the News

Periostat^®+ SRP
Treating Adult Periodontal Disease

The etiology of periodontitis is multifactorial; its nature and severity are determined by complex interactions between microbial factors and a susceptible host. Although pathogenic bacteria in the gingival sulcus are necessary for periodontitis, bacteria alone are not sufficient for the progression of the disease. Research during the last 20 years has indicated that the body’s own local and systemic response to bacterial toxins is a major determinant of the severity of periodontitis. The end result of the interaction between the infectious bacteria and the host response is the bone and soft tissue destruction and attachment loss that characterize periodontitis.

Current first-line therapies for periodontitis primarily address the bacterial component of the disease. The current nonsurgical standard of periodontal care is scaling and root planing (SRP), a mechanical intervention designed to physically remove bacteria and its deposits from the surface of the tooth. If indicated, SRP may be supplemented by antimicrobial drugs, either locally or systemically.

Periostat^® is the first therapeutic agent designed to modulate the host response and, when prescribed as an adjunct to SRP, has been shown to help slow the progression of adult periodontitis.

Periostat^® works by reducing the activity of host-derived enzymes, such as collagenase, which have been shown to be associated with the destruction of the periodontal support structures during the progression of adult periodontitis. Periostat^® is administered systemically, offering the additional advantage of being able to treat all the tooth sites simultaneously — a whole-mouth approach to the management of the host response.

The daily dosing regimen of Periostat^® (20 mg twice daily) has been studied extensively and has been shown to produce plasma levels of doxycycline that are substantially lower than that required to induce an antimicrobial effect — in other words, a subantimicrobial dose. When administered according to the dosage regimen prescribed in the labeling, Periostat^® has been shown to have no detrimental effect on the susceptibility of the microflora to doxycycline and other common antibiotics.

Extensive clinical studies have shown that the use of Periostat^® as an adjunct to SRP is more effective than SRP alone in reducing probing pocket depth and enhancing clinical attachment level gain in patients with adult periodontitis.

In clinical trials, adverse reactions to Periostat^® were similar to taking a placebo. Don’t take Periostat^® if you are pregnant, nursing, or if you’re hypersensitive to tetracyclines. For more information, please refer to the Periostat^® Full Prescribing Information.

Treatment with Subantimicrobial Dose Doxycycline Improves the Efficacy of Scaling and Root Planing in Patients with Adult Periodontitis

J. G. Caton, S. G. Ciancio, T. M. Bileden, M. Bradshaw, R. J. Crout, A. F. Hefti, J. M. Massaro, A. M. Polson, J. Thomas, and C. Walker

Background: In a previous study, subantimicrobial dose doxycycline (SDD) significantly improved clinical parameters associated with periodontal health in patients with adult periodontitis (AP) when used as an adjunct to a maintenance schedule of supragingival scaling and dental prophylaxis. In this double-blind, placebo-controlled, parallel-group, multicenter study, the efficacy and safety of SDD were evaluated in conjunction with scaling and root planing (SRP) in patients with AP.

Methods: Patients (n=190) received SRP at the baseline visit and were randomized to receive either SDD 20 mg BID or placebo BID for 9 months. Efficacy parameters included the per-patient mean changes in clinical attachment level (CAL) and probing depth (PD) from baseline, the per-patient percentages of tooth sites with attachment loss (AL) > 2 mm and > 3 mm from baseline, and the per-patient percentage of tooth sites with bleeding on probing. Prior to analysis, tooth sites were stratified by the degree of disease severity evident at baseline.

Results: In tooth sites with mild-to-moderate disease and severe disease (n=183, intent-to-treat population), improvements in CAL and PD were significantly greater with adjunctive SDD than with adjunctive placebo at 3, 6, and 9 months (all P < 0.05). In tooth sites with severe disease, the per-patient percentage of sites with AL > 2 mm from baseline to month 9 was significantly lower with adjunctive SDD than with adjunctive placebo (P < 0.05). Improvements in clinical outcomes occurred without detrimental shifts in the normal periodontal flora or the acquisition of doxycycline resistance or multiantibiotic resistance. SDD was well tolerated, with a low incidence of discontinuations due to adverse events.

Conclusion: The adjunctive use of SDD with SRP is more effective than SRP alone and may represent a new approach in the long-term management of AP. J Periodontol. 2000;71:521-532.

Key Words: Doxycycline/therapeutic use; periodontitis/drug therapy; double-blind method; placebo-control study; multicenter studies; parallel-group study

Long-term Treatment With Subantimicrobial Dose Doxycycline Exerts No Antibacterial Effect on the Subgingival Microflora Associated With Adult Periodontitis

C. Walker, J. Thomas, S. Nangó, J. Lennon, J. Wetzel, and C. Powala

Background: The purpose of this study was to determine whether treatment with subantimicrobial dose doxycycline (SDD), 20 mg BID, exerted an antimicrobial effect on the microflora associated with adult periodontitis.

Methods: Following the approval of the protocol and informed consent forms by the respective IRBs at the University of Florida and West Virginia University, 76 subjects with adult periodontitis were entered and randomly assigned to receive SDD or placebo. A split-mouth design was utilized, with each subject receiving subgingival scaling and root planing (SRP) in two quadrants immediately following baseline data collection, while the remaining two quadrants were left unscaled (non-SRP). Microbial samples were collected prior to treatment, after 3, 6, and 9 months of treatment, and after 3 months of no treatment. The samples were examined by microscopy and by enumeration on selective and nonselective media.

Results: All treatments resulted in statistically significant decreases in the proportions of spirochetes and motile rods (P < 0.05) and in an increase in the proportion of coccoid forms (P < 0.0001) relative to baseline. No between-treatment differences were detected between the SDD and placebo treatments in either the SRP or non-SRP design, with the exception of the small and large spirochetal groups. The spirochetal proportions present in the SDD group were significantly lower (P < 0.05) than the paired placebo group during the 9-month treatment and were preceded by a significant decrease (P < 0.01) in the proportion of microbiologic sample sites that bled on probing. No between-treatment differences were detected in any of the other microbial parameters.

Conclusion: The microbial differences observed were attributed to the anticollagenase and anti-inflammatory properties of SDD and not to an antimicrobial effect. J Periodontol. 2000;71:1465-1471.

Key Words: Periodontitis/microbiology; doxycycline/therapeutic use; clinical trials; controlled trials

The “Cyclic” Regimen of Low-Dose Doxycycline for Adult Periodontitis: A Preliminary Study

R. J. Crout, H. M. Lee, K. Schroeder, H. Crout, N. S. Ramamurthy, M. Wiener, and L. M. Golub

Specially formulated low-dose doxycycline (LDD) regimens have been found to reduce collagenase activity in the gingival tissues and gingival crevicular fluid (GCF) of adult periodontitis subjects in short-term studies. In the current, double-blind, placebo-controlled study, adult periodontitis patients were administered a “cyclical” regimen of either LDD or placebo capsules for 6 months, and various clinical parameters of periodontal disease severity, both collagenase activity and degradation of the serum protein, and α₁-PI in the GCF were measured at different time periods. No significant differences between the LDD- and placebo-treated groups were observed for plaque index and gingival index. However, attachment levels, probing depth, and GCF collagenase activity and α₁-PI degradation were all beneficially and significantly (P < 0.05) affected by the drug regimen. We propose: 1) that LDD inhibits tissue destruction in the absence of either antimicrobial or significant anti-inflammatory efficacy; and 2) that long-term LDD could be a useful adjunct to instrumentation therapy in the management of the adult periodontitis patient. J Periodontol. 1996;67:506-514.

Key Words: Doxycycline; gingival crevicular fluid; periodontitis/diagnosis; collagenases; proteinase inhibitors; periodontal attachment; double-blind studies

Adjunctive Treatment with Subantimicrobial Doses of Doxycycline: Effects on Gingival Fluid Collagenase Activity and Attachment Loss in Adult Periodontitis

L. M. Golub, T. F. McNamara, M. E. Ryan, B. Kohut, T. Bileden, G. Payonk, T. Sipos, and H. J. Baron

Objectives: The therapeutic effects of doxycycline and other tetracyclines in the treatment of periodontitis involve, at least in part, mechanisms that are unrelated to their antimicrobial activity. Previous clinical studies have shown that doxycycline administered orally — at doses below those needed for antimicrobial efficacy — to human subjects with adult periodontitis resulted in significantly reduced collagenase activity in gingival crevicular fluid (GCF) and in extracts of inflamed gingival tissues. The purpose of the present study was to identify clinically effective dosing regimens using subantimicrobial dose doxycycline (SDD) as an adjunctive therapy in patients with adult periodontitis.

Material and Methods: A total of 75 adult men and women qualified for enrollment into the 3-part, placebo-controlled, double-blind, parallel-group study. Patients were stratified based on repeatedly exhibiting pathologic levels of periodontal attachment (Alv) and GCF collagenase activity at several appointments prior to baseline. Patients received scaling and prophylaxis, then 1 of 5 treatment schedules for 12 weeks (part I), followed by a 12-week period of no drug therapy (part II), a second scaling and prophylaxis, and 12 additional weeks of treatment (part III). Primary determinants of efficacy included reductions in GCF collagenase activity and changes in relative Alv.

Results: 66 patients completed the first 12 weeks (part I) of the 3-part, 36-week study; 51 patients completed the entire 36-week study. From baseline to week 12 (part I), treatment with specially formulated SDD capsules (20 mg) 2x daily (1x every 12 h) for up to 12 weeks was shown to significantly reduce GCF collagenase activity and to improve Alv; effects not seen in patients treated with placebo. Continuous drug therapy over the 12-week treatment period was needed to maintain and maximize the reduction in GCF collagenase and the improvement in Alv. Improvements in periodontal disease parameters occurred without the emergence of doxycycline-resistant microorganisms. In patients administered an “on-off-on” regimen of SDD over 36 weeks (parts I-III), essentially no attachment loss occurred in patients receiving the highest of these SDD regimens (20 mg 2x daily during part I and 20 mg 1x daily in part III), whereas patients administered placebo capsules experienced a mean attachment loss of approximately 0.8 mm at the 24- and 36-week time periods.

Conclusion: Doxycycline administered at subantimicrobial doses led to improvements in disease parameters with no apparent side effects, and it appears to have significant potential as an oral adjunctive therapy in the long-term management of adult periodontitis. J Clin Periodontol. 2001;28:146-156.

Long-term Use of Subantimicrobial Dose Doxycycline Does Not Lead to Changes in Antimicrobial Susceptibility

J. Thomas, C. Walker, and M. Bradshaw

Background: Adjunctive subantimicrobial dose doxycycline (SDD) with scaling and root planing leads to improved clinical parameters of adult periodontitis, but it has raised questions about potential changes in antibiotic susceptibility of the host microflora. These 4 studies assessed whether long-term SDD changes antibiotic susceptibility of the oral microflora in adults with periodontitis.

Methods: In studies 1 and 2, adult patients with periodontitis were randomized to receive SDD 10 mg QD, 20 mg QD, 20 mg BID, or placebo. In study 3, patients were randomized to receive SDD 20 mg BID or placebo. No medication was administered in study 4, a follow-up to study 3. Subgingival plaque samples were collected at baseline (all studies) and at 12, 15 to 18, and 24 months (study 1); 12, 18, and 27 months (study 2); 3, 6, and 9 months (study 3); and 3 months poststudy 3 (study 4). Antimicrobial susceptibility of isolated bacteria was assessed by: 1) minimum inhibitory concentration (MIC) levels (studies 1 and 2); 2) cross-resistance to nontetracycline antibiotics (studies 2 and 3) and 3) the proportion of doxycycline-resistant isolates (studies 3 and 4).

Results: Organism MIC levels remained constant among all treatment groups at 18 and 24 months compared with baseline (study 1). Observed changes in susceptibility at 12 and 18 months for the 20-mg groups were attributed to the limited number of isolates tested (study 1). There were no statistically significant differences in the proportion of doxycycline-resistant isolates among treatment groups (studies 3 and 4), and no evidence of multi-antibiotic resistance (studies 3 and 4) or cross-resistance (studies 2 and 3) at any time point.

Conclusion: Long-term SDD does not contribute to changes in antibiotic susceptibility. J Periodontol. 2000;71:1472-1483.

Key Words: Doxycycline/therapeutic use; drug resistance, microbial; antibiotics/therapeutic use; periodontitis/drug therapy; dose-response relationship; drug; comparison studies

Subantimicrobial Dose Doxycycline as an Adjunct to Scaling and Root Planing: Post-treatment Effects

J. G. Caton, S. G. Cilancio, T. M. Bileden, M. Bradshaw, R. J. Crout, A. F. Hefti, J. M. Massaro, A. M. Poison, J. Thomas, and C. Walker

Background/objective: Subantimicrobial dose doxycycline (SDD 20 mg BID) plus scaling and root planing (SRP) significantly improved clinical attachment level (CAL) and reduced probing depth (PD) compared with placebo plus SRP in double-blind, placebo-controlled, multicenter study of patients with adult periodontitis (AP). In a study conducted as a follow-up, the posttreatment effects of SDD were assessed in patients who completed the SRP study.

Methods: The SRP study was a 9-month, active-treatment study and the follow-up was a 3-month, no treatment study. In the SRP study, tooth sites in qualifying quadrants were scaled and root planed and patients were randomized to receive SDD 20 mg or placebo twice daily. In the follow-up, patients received no study drug; investigators and patients remained blinded to the previous treatment group assignments. Efficacy measures included the change in CAL and PD from baseline values determined at the start of the SRP study in tooth sites stratified by baseline PD (ie, 0-3 mm, 4-6 mm, = 7 mm). Safety was evaluated using adverse event data and the results of clinical laboratory tests, oral pathology examinations, and microbiological assessments.

Results: Within each disease stratum, the incremental improvements in PD and CAL demonstrated in the SDD group over 9 months of active treatment were maintained through 3 additional months of no treatment. Treatment cessation did not result in an accelerated regression of periodontal health. No differences in the incidence of adverse events (including those related to infection) or laboratory or microbiological parameters were noted between the SDD group and the placebo group.

Conclusion: The administration of SDD 20 mg BID for a period of up to 9 months is not associated with rebound effects or delayed or negative after-effects for a 3-month period after cessation of therapy. J Clin Periodontol. 2001;28:782-789.

Key Words: doxycycline; subantimicrobial; matrix metalloproteinases; periodontitis; scaling and root planing; posttreatment

* SRP = Scaling and root planing (a professional deep cleaning procedure)

Please see Full Prescribing Information for adverse reactions,
warnings, and contraindications.