Tetracyclines have long been considered useful adjuncts in peridontal therapy based on their antimicrobial efficacy against putative periodontopathogens. However, recently these drugs were found to inhibit mammalian collagenases and several other matrix metalloproteinases (MMPs) by a mechanism independent of their antimicrobial activity. Evidence is presented that this property may be therapeutically useful in retarding pathologic connective tissue breakdown, including bone resorption. The experiments leading to this discovery are described and possible mechanisms are addressed, including the specificity of tetracyclines' anti-collagenase activity, the role of the drugs' metal ion (Zn2+, Ca2+)-binding capacity, and the site on the tetracycline molecule responsible for this nonantimicrobial property. Of extreme interest, the tetracycline molecule has been chemically modified in multiple ways, generating a new family of compounds called CMTs (chemically modified tetracyclines) that lack antimicrobial but still retain anti-collagenase activity. The first of these CMTs, 4-de-di-methylaminotetracycline, was found not to produce a major side-effect of antimicrobial tetracycline therapy--its administration to experimental animals did not result in the emergence of tetracycline-resistant microorganisms in the oral flora and gut. Numerous examples of the clinical potential of this non-antimicrobial property of tetracyclines in the treatment of periodontal and several medical diseases (e.g., sterile corneal ulcers, rheumatoid arthritis, skin bullous lesions, tumor-induced angiogenesis and metastasis) are discussed.
Tetracyclines are now recognized to have non-antimicrobial properties with therapeutic potential--for example, these agents can inhibit pathologic collagenolysis by blocking mammalian collagenases and other matrix-degrading metalloproteinases. In the current study, adult human subjects with moderate chronic periodontitis were administered specially formulated capsules of doxycycline, containing lower-than-usual amounts of this semi-synthetic tetracycline, on a daily basis for 2 weeks prior to a full-thickness flap procedure; control subjects were administered placebo capsules. The gingiva excised during this surgical procedure were extracted, the extracts partially purified and analyzed for collagenase activity using [3H-methyl] collagen as substrate and the techniques of SDS-PAGE/fluorography or liquid scintillation spectrometry. In the absence of any drug pre-treatment, or after a 2-wk regimen of placebo capsules, the gingival extracts exhibited pathologically-excessive mammalian collagenase activity. The 2-wk regimen of low-dose doxycycline capsules reduced this activity by approximately 60-80% (p less than 0.05 and less than 0.01, respectively); in vitro exposure of the gingival extract to doxycycline also inhibited its collagenase activity. Collagenase activity in the crevicular fluid of periodontal pockets of an additional group of subjects was also significantly reduced, as was the severity of inflammation at the same gingival sites. The results suggest that a regimen of low-dose doxycycline capsules may provide a safe (other studies indicate that this regimen may not induce tetracycline resistance in the subgingival plaque) and effective adjunct to instrumentation therapy in the management of pathologic collagenolysis in the periodontal patient. However, further studies are necessary to confirm this hypothesis.
Doxycycline administered at subantimicrobial doses led to improvements in disease parameters, with no apparent side effects, and appears to have significant potential as an oral adjunctive therapy in the long-term management of adult periodontitis.
Tetracyclines (including the semi-synthetic analogues, minocycline and doxycycline) are considered useful adjuncts in periodontal therapy because they suppress Gram-negative periodontopathogens. Recently, these antibiotics were found to inhibit mammalian collagenase activity, a property which may also be of therapeutic value. It has been suggested that the anti-collagenase properties of the tetracyclines are independent of their antibiotic efficacy. To advance this hypothesis further, we chemically converted tetracycline hydrochloride to its non-antimicrobial analogue, de-dimethylaminotetracycline. This chemically-modified tetracycline (CMT), although no longer an effective antibiotic, was found to inhibit the in vitro activity of collagenase from partially purified extracts of human rheumatoid synovial tissue and rachitic rat epiphysis. In a preliminary in vivo study, pathologically-excessive collagenase in skin and gingiva was induced by rendering adult male rats diabetic, and the oral administration of CMT to these rats significantly reduced the excessive collagenase activity in both tissues. Moreover, CMT administration did not affect the severe hyperglycemia in these rats but did prevent, at least in part, the diabetes-induced loss of body weight, skin weight, and skin collagen mass; these effects suggest a lack of toxicity in this animal model. A proposed clinical advantage of CMT over conventional tetracyclines, in the treatment of diseases characterized by excessive collagenolytic activity, is the lack of development of antibiotic-resistant micro-organisms during prolonged use. However, the consideration of clinical trials to support this hypothesis must await further laboratory and extensive toxicity tests.
Recently, a new mechanism was proposed to explain the therapeutic efficacy of tetracyclines in periodontal disease— that specifically these antibiotics directly inhibit the activity of collagenase (and possibly other collagenolytic enzymes) produced by the host tissues resulting in a reduced rate of collagen breakdown (Golub et al. 1983). In the current studies, the effect of tetracyclines (minocycline, doxycycline, tetracycline) on collagenolytic enzyme activity was examined in human periodontal pockets and in several animal systems. In the clinical studies, gingival crevicular fluid (GCF) was collected on filter paper strips from individual periodontal pockets, the volume measured with the Periotron 6000, and the Gingival Index and pocket depth scored immediately thereafter at the same sites. The strips were incubated with [3H‐methyi] collagen maintained in solution (or with 14C‐glycine labeled collagen Fibrils), and the radiolabeled collagen degradation products measured in a liquid scintillation spectrometer, Using the techniques of SDS‐PAGE and fluorography, the GCF was observed to generate collagen degradation products characteristic of those produced by mammalian collagenase, a finding consistent with previous studies. Both minocycline and tetracycline therapy reduced GCF collagenolytic activity about 70% during the initial weeks of treatment; the clinical parameters also showed improvements at the same time periods. This reduction in collagenolytic activity had largely regressed by 5 weeks after terminating tetracycline therapy and by 19 weeks after minocycline therapy, in the absence of other forms of periodontal treatment. In a preliminary study, 50 days of doxycycline treatment also reduced GCF collagenase activity, an effect which persisted for at least 2 months (but less than 1 year) after terminating its administration. In several studies involving experimental animals, the tetracyclines (1) in vivo, were found to reduce the pathologically excessive collagenase activity in gingiva and skin of diabetic rats; and (2) in vitro, directly inhibited the activity of collagenases from rat PMNL's and rabbit chondrocytes. The data in the current and our previous studies (Golub et al. 1983, Gomes, Golub & Ramamurthy 1984) continue to support the hypothesis that tetracyclines, by directly inhibiting collagenolytic enzyme(s) activity, may be therapeutically useful in treating diseases, such as periodontitis, characterized by excessive collagen breakdown.
Tetracyclines have been widely used as adjuncts in periodontal therapy due to the antimicrobial efficacy of these drugs. Recently, their ability to inhibit host-derived matrix metalloproteinases (collagenase and gelatinase) and bone resorption in organ culture has also been invoked as a therapeutic rationale. The current study was undertaken to determine whether tetracyclines can inhibit alveolar bone loss in vivo due to a non-antimicrobial action of these drugs. Experimental periodontitis was induced by inoculating adult, male Sprague-Dawley rats with P. gingivalis (strain 381) following kanamycin/ampicillin pretreatment. Doxycycline, non-antimicrobial chemically-modified tetracycline (CMT-1) and vehicle alone were administered daily to 3 infected groups of rats (n = 6 rats per group; each group housed in a sterilized inflatable isolator) beginning 10 days after P. gingivalis inoculation. The control group (n = 6; non-infected rats) received only vehicle. After 5 weeks of daily drug administration by gastric intubation, the experiment was terminated and blood samples were taken from each animal to determine antibody levels against P. gingivalis. Plaque samples were collected from each group of animals before and after P. gingivalis inoculation and at the end of the experiment for microbiological examination. The jaws were removed from each rat, defleshed and then analyzed morphometrically and radiographically to assess bone loss. Serum antibody levels against P. gingivalis were significantly elevated in the 3 infected groups compared to the non-infected controls. This, together with the microbiologic findings, indicated that these groups of rats were infected with P. gingivalis.(ABSTRACT TRUNCATED AT 250 WORDS)
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