Chemotherapeutic agent to slow or arrest periodontitis
Product name: Periostat (doxycycline hyclate)
Manufacturer: CollaGenex Pharmaceuticals, 41 University Drive, Suite 200, Newtown, Pa. 18940, 1-888-339-5678, "www.periostat.com"
ADA Acceptance: Received ADA Seal of Acceptance in June 2001
Other ADA-Accepted products in this category: Atridox (manufactured by Atrix Laboratories Inc., Fort Collins, Colo., and distributed by CollaGenex Pharmaceuticals)
Periostat is approved by the U.S. Food and Drug Administration, or FDA, as an adjunct to scaling and root planing, or SRP, to promote attachment level gain and to reduce pocket depth in patients with adult periodontitis. Each Periostat capsule/tablet contains doxcycline hyclate equivalent to 20 milligrams of doxycycline. Doxycycline is synthetically derived from oxytetracycline. One tablet of Periostat is taken orally twice a day.
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Efficacy Data:
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CollaGenex submitted two independent, placebo-controlled, clinical studies examining the effect of Periostat in combination with SRP vs. placebo in combination with SRP on subjects with periodontitis. The first study involved a total of 190 subjects. The treatment period was nine months. This study found statistically significant differences in the mean per-patient average attachment level with Periostat plus SRP compared with placebo plus SRP for baseline probing depths of 4 to 6 millimeters (an average attachment level gain of 0.17 mm) and > 7 mm (an average attachment level gain of 0.38 mm).1 Additionally, this study found statistically significant differences in mean per-patient average probing depths with Periostat plus SRP compared with placebo plus SRP for baseline probing depths of 0 to 3 mm (an average pocket depth reduction of 0.11 mm), 4 to 6 mm (an average pocket depth reduction of 0.26 mm) and > 7 mm (an average pocket depth reduction of 0.48 mm).1
The second study evaluated the effect of Periostat on 209 subjects. The study’s design was identical to that of the first,1 and the results, similarly, showed that the Periostat-plus-SRP group had a significantly greater improvement in attachment level than did the placebo-plus-SRP group for all baseline probing depths 0 to 3 mm (an average attachment level gain of 0.15 mm), 4 to 6 mm (an average attachment level gain of 0.33 mm) and > 7 mm (an average attachment level gain of 0.50 mm) (CollaGenex Pharmaceuticals, unpublished data, 2001; data on file with the ADA Council on Scientific Affairs). Additionally, the Periostat-plus-SRP group showed a significantly greater reduction in average probing depths compared to the placebo-plus-SRP group for baseline probing depths of 0 to 3 mm (an average pocket depth reduction of 0.13 mm), 4 to 6 mm (an average pocket depth reduction of 0.33 mm) and > 7 mm (an average pocket depth reduction of 0.54 mm) (CollaGenex Pharmaceuticals, unpublished data, 2001; data on file with the ADA Council on Scientific Affairs).
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Considerations for Acceptance:
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Periostat was evaluated by the Council on Scientific Affairs using the ADA Acceptance Program Guidelines for Chemotherapeutic Agents to Slow or Arrest Periodontitis.
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Safety Data and Toxicity:
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Periostat was found to be well-tolerated when taken at the recommended dosage of 20 mg twice a day for up to 12 months. No effect of Periostat treatment on hematology, clinical chemistry and urinalysis was found. The recommended dose of Periostat is below the dose required for antimicrobial activity. Periostat is meant to be taken at this subantimicrobial dose for up to nine months and, therefore, studies were completed to examine the effect of this dosage regimen on the induction of antibiotic resistant microbes. These 12-month studies found no significant alterations in distribution of oral flora, no susceptibility of oral flora to antibiotics, and no induction or selection of cross-resistance of oral flora to antibiotics. An additional nine-month clinical study found that Periostat had no antibacterial effect on intestinal or vaginal microflora (C. Walker, Ph.D., and colleagues, unpublished data, 2001).
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Mechanism of Action:
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The mechanism of action of Periostat is thought to be inhibition of collagenase activity. Doxycycline has been shown to attenuate elevated collagenase activity in the gingival crevicular fluid of patients with adult periodontitis.2 By reducing collagenase activity, Periostat is thought to arrest the destruction of the periodontium.
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Contraindications and Warnings:
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People who have demonstrated a hypersensitivity to any of the tetracyclines should not use Periostat. Tetracyclines should not be used by pregnant or nursing women or by children younger than eight years of age. Some people taking tetracyclines may develop an exaggerated sunburn reaction.
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Benefits of Use:
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Periostat treatment significantly improved the results of SRP in the treatment of periodontitis. Periostat works by reducing enzymes that break down the periodontium. This is a novel mechanism of action for the treatment of periodontitis. Systemic delivery treats the whole mouth.
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FOOTNOTES
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"Periostat has been shown to help stop the progression of periodontitis when used as directed as an adjunct to scaling and root planing, in a conscientiously applied program of oral hygiene and regular professional care." —Council on Scientific Affairs, American Dental Association
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REFERENCES
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- Caton JG, Ciancio SG, Blieden TM, et al. Treatment with subantimicrobial dose doxycycline improves the efficacy of scaling and root planing in patients with adult periodontitis. J Periodontol 2000;71(4):521–32.[Medline]
- Golub LM, Lee H., Greenwald RA, et al. A matrix metalloproteinase inhibitor reduces bone-type collagen degradation fragments and specific collagenases in gingival crevicular fluid during adult periodontitis. Inflamm Res 1997;46:310–9.[Medline]
Treatment of periodontitis
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MECHANICAL TREATMENT
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Mechanical treatment of periodontitis includes several elements. Daily home care by the patient is essential and includes brushing, interdental cleaning, rinsing and, occasionally, oral irrigation. Professional care includes scaling and root planing (with or without subgingival irrigation), surgery, and periodontal maintenance procedures.
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CHEMOTHERAPEUTIC TREATMENT
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Several classes of antibiotics have been used for the treatment of periodontitis in combination with mechanical therapy. Locally applied antimicrobials (such as tetracyclines or chlorhexidine) are used alone or in combination with mechanical therapy. Doxycycline hyclate, a semisynthetic tetracycline, is the active ingredient in two ADA-Accepted products for the treatment of periodontitis, Atridox (manufactured by Atrix Laboratories, Fort Collins, Colo., and distributed by CollaGenex Pharmaceuticals, Newtown, Pa.) and Periostat (CollaGenex Pharmaceuticals). Although both contain the same active ingredient, their putative mechanisms of action for treating periodontal disease are very different. At low (subantimicrobial) doses, doxycycline acts as an inhibitor of the enzyme collagenase. At higher (antimicrobial) doses, doxycycline acts as a broad-spectrum antibiotic that inhibits bacterial protein synthesis through disruption of transfer RNA and messenger RNA.
Arestin (OraPharma Inc., Warminster, Pa.) was approved by the U.S. Food and Drug Administration, or FDA, in February 2001. This 1-milligram minocycline hydrochloride micro-sphere can be placed directly in the infected periodontal pocket. Arestin is an adjunctive treatment for reduction of pocket depth in patients with adult periodontitis after scaling and root planing.
Periostat, approved by the FDA in September 1998, is a subantimicrobial dose of doxycy-cline that is used as an adjunct to scaling and root planing. Periostat acts systemically at a dose of doxycycline that is below the concentration required to inhibit microorganisms commonly associated with periodontitis. At this dose, doxycycline inhibits the activity of collagenase, a matrix metalloprotease that degrades collagen. Collagen is the main protein in the extracellular spaces of connective tissue. Collagen forms insoluble fibers with a high tensile strength that make up the structural basis of the periodontium. The tissue destruction associated with periodontitis correlates with an increase in collagenase activity. It is thought that Periostat acts by inhibiting the breakdown of collagen.
Atridox was approved by the FDA in September 1998. Atridox couples 10 percent doxycycline hyclate with the Atrigel biodegradable polymer drug delivery system. Atridox is applied as a gel and placed directly into infected periodontal pockets, where it solidifies. An antimicrobial dose of doxycycline is released locally over a seven-day period. No anesthetic is necessary, and because Atrigel is biodegradable, it does not have to be removed. Atridox has been shown to be comparable to scaling and root planing for reduction of pocket depth and improvement of attachment level.1
PerioChip (manufactured by Perio Products Ltd., Jerusalem, and available through Dexcel Pharma Inc., Edison, N.J.) was approved by the FDA in May 1998. PerioChip is a biodegradable chip made of hydrolyzed gelatin containing 2.5 mg of chlorhexidine gluconate. PerioChip is indicated as an adjunct to scaling and root planing for reduction of pocket depth in patients with adult periodontitis and as part of a periodontal maintenance program.
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REFERENCES
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- Garrett S, Johnson L, Drisko CH, et al. Two multi-center studies evaluating locally delivered doxycycline hyclate, placebo control, oral hygiene, and scaling and root planing in the treatment of periodontitis. J Periodontol 1999;70(5):490–503[Medline]
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Efficacy Data:
Considerations for Acceptance:
