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Notes: Abstract Histatins, histidine-rich proteins found within parotid and submandibular secretions, are a novel class of endogenous peptides with antimicrobial properties. This masked, randomized, placebo-controlled preclinical investigation examined the effect of 3 topical histatins on the development of plaque and gingivitis in beagle dogs. 16, female, 1-year-old beagles were brought to optimal gingival health by mechanical scaling and polishing followed by rigorous daily tooth brushing. At the conclusion of this pretreatment period, dogs were randomly divided into 4 groups for the application of test formulations, and were placed on a plaque-promoting diet, Test agents included 3 synthetic salivary histatins (histatin 5, P-113 and P-113D) which were incorporated in hydroxypropyl methylcellulose gel at a concentration of 0.125%, and a placebo, or negative control, which was the gel vehicle alone. Throughout the 10-week treatment period, test formulations (2.0 ml) were applied 2xdaily to all premolar teeth using a Monojet syringe. Plaque formation and gingival inflammation were assessed using the plaque (PI) and gingival (GI) indices on days 0, 7, 14, 21, 28, 42, 56 and 70. Furthermore, bleeding to probing was recorded as a percent of sites (%BOP) and according to the modified sulcus bleeding index (mSBI). Comparisons among groups and between group pairs (active versus placebo) were made with Kruskal-Wallis tests with the average of data over the interval, days 14–42, being the primary focus of the analysis. From baseline to day 7, all groups expressed similar indices. Thereafter, overall significant differences among the groups were noted at day 42 for PI, at days 21, 28, 42 and 70 for GI, and at days 14 and 28 for %BOP (p〈0.05). In particular, beagles treated with P-113 demonstrated significantly lower PI scores at day 42 (p〈0.05), significantly lower GI scores from days 21 through 42 (〈0.05), and significantly lower %BOP scores at days 14 and 28 (p〈0.05) compared to beagles treated with placebo. Beagles treated with P-113D exhibited significantly lower GI at day 42 compared to the placebo (p〈0.05). For the primary analysis conducted over the midtreatment interval (days 14–42), significant differences were detected for all parameters except mSBI (p〈0.05). Accordingly, significantly lower PI scores were found for P-113, lower GI scores for P-113 and P-113D, and lower %BOP for P-113 and P-113D compared to placebo (p〈0.05). These data indicate that in the beagle model, salivary histatins, P-113 and P-113D, topically applied, can significantly reduce clinical signs of plaque formation and gingival inflammation.

Notes: The reported therapeutic benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) in slowing periodontal disease progression appear intimately linked to the effective inhibition of local prostaglandin synthesis. This randomized, partially double-blind, controlled trial was conducted to evaluate the pharmacodynamic effects of the NSAID, ketoprofen (KTP), on gingival crevicular fluid (GCF) prostanoids. 42 subjects, ages 35–57 years, with moderate to advanced adult periodontitis were recruited and monitored for 22 days. On day 1, subjects were randomized for 1 of 5 treatments: i) 0.5% KTP gel; ii) 1.0% KTP gel; iii) 1.0% KTP alternate gel; iv) 2.0% KTP gel; v) 25 mg KTP capsule (positive control). Subjects applied 1 ml of gel topically to their gingiva or administered one capsule p.o., b.i.d. for 14.5 days. GCF samples were collected from posterior, interproximal sites on days 1 (pre-dosing; 1, 2, 3, 6 h), 8 (pre-dosing; 2 h), 15 (pre-dosing; 2 h) and 22 (post-treatment). GCF levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were determined using RIA, and expressed in ng/ml and % reduction from baseline (%Effect). Neither a significant difference among groups nor a dose response in % effect for either prostanoid was evident, both overall and among cohorts with elevated baseline mediator levels ([PGE2]〉34 ng/ml; [LTB4]〉300 ng/ml). When data were combined from all groups, significant (p〈0.01) % reductions in GCF PGE2 were noted at 1 and 2 h post-dosing (29% and 24%, respectively). In comparing topical versus systemic formulations, all topical formulations were as equipotent as systemic dosing in altering local prostaglandin levels despite lower KTP exposures with gel treatments. These data indicate that both topical and systemic KTP therapies pharmacodynamically reduce GCF PGE2 levels in adult periodontitis subjects, allowing for potential inhibition of disease progression.

Notes: Background: Our research group has recently reported that exogenously applied histatins can inhibit plaque accumulation and gingival inflammation in a preclinical canine model (Paquette et al. 1997).Objectives: The aims of the present double-blinded, randomized, controlled clinical trial were to evaluate the safety and toxicity of three histatin (P-113) concentrations in gel formulations, and to assess potential clinical benefit on the development of gingivitis (partial mouth design).Material and methods: One hundred and six healthy subjects were recruited and brought to optimal gingival health (GI 〈 0.5) prior to treatment initiation. At baseline, eligible subjects were randomized for one of the following treatments: (1) placebo; (2) 0.0625% P-113; (3) 0.125% P-113; and (4) 0.375% P-113. Patients self-applied gels twice daily for 29 days to the maxillary right quadrant with the use of customized stents. In addition, patients deferred all oral hygiene procedures within this quadrant for the duration of the treatment period. Safety was assessed in terms of physical and oral examinations, clinical laboratory testing and recording of adverse events. Clinical indices were measured weekly and included gingival index (GI), plaque index (PI) and %BOP.Results:  All study formulations were well tolerated by patients, and no differences in adverse event occurrences were noted among treatment groups, including taste alteration or staining. For the intent-to-treat population, significantly smaller %BOP changes were noted in subjects treated with 0.0625, 0.125 and 0.375% P-113 gels (17.4, 18.18 and 17.9%, respectively) versus placebo (28.0%) (p 〈 0.05) at day 29. When groups were compared in terms of per cent responders (change in %BOP 〈 15 or 〈 20%), P-113 treatment groups exhibited a higher frequency of response, especially for the 0.0625 and 0.125% P-113 formulations (p 〈 0.05). Although no statistically significant intergroup differences were noted for changes in GI or PI among all subjects (intent-to-treat population), significantly smaller changes in PI at day 22 were observed among compliant individuals (defined as subjects using 〉 60% of the target gel mass) administering P-113 gels as compared with compliant placebo subjects (p 〈 0.05).Conclusions: These data indicate safety and tolerance of P-113 gels for topical oral use in human subjects. These data also suggest that P-113 gels administered twice daily may reduce experimental gingivitis as measured with bleeding on probing in humans.

Notes: There is increasing interest in how pathways of tissue destruction around dental implants are similar as for teeth and how these pathways can be modulated to slow loss of supporting bone. The purposes of this study were to develop a short-term animal model to study the effect of the nonsteroidal anti-inflammatory drug flurbiprofen, on slowing the rate of induced peri-implant bone resorption. A total of 20 cylindrical titanium implants were placed in 2 beagle dogs using a low-trauma surgical technique. During the 3-month healing period without functional loading of the implants, daily oral hygiene was performed to maintain a Gingival Index of 0 to 0.5. At completion of the healing period, a baseline evaluation was performed which included the uptake of the bone-seeking radiopharmaceutical (BSRU)99mtechnetium-tin-diphosphonate (99mTc-Sn-MDP) in peri-implant bone and standardized radiographs. Peri-implantitis was induced with 4-O silk ligatures, cessation of oral hygiene and soft diet. One beagle was given 0.02 mgikg of flurbiprofen by mouth; the other received a placebo. BSRU and radiographic height of bone were remeasured to calculate the rate of bone loss during the 60-day treatment period. The percent rate of bone loss during the study period was calculated from the radiographs using a computer-assisted method. The radiopharmaceutical uptake for the flurbiprofen-treated implants remained unchanged. However, BSRU for placebo-treated implants was significantly increased from baseline. Radiographic measurements of bone height revealed that the mean rate of bone loss around implants in the flurbiprofen-treated dog (0.066±0.351%/month) was significantly lower than the rate around implants in the placebo-treated dogs (5.729±0.384%/month) over the 60-day treatment period. These data indicate that peri-implant bone loss can be rapidly induced and measured in the beagle and that flurbiprofen. administered orally, can significantly decrease the rate of induced peri-implant bone loss.

Notes: This study involved histometry of the healed tissues around submerged and nonsubmerged dental implants in beagle dogs. In a split-mouth design, 19 submerged and 19 nonsubmerged commercially pure titanium implants, titanium plasma-sprayed in the bone anchoring part and smooth in the transmucosal portion were placed in the mandibles of 6 dogs. Oral hygiene was performed 3 times weekly. After 3 months of healing, transmucosal abutments were inserted in the submerged implants. Six weeks after second stage surgery, the dogs were sacrificed and specimens obtained and processed for histology and histometry. Using a light microscope and a digitizing pad, the distance from implant top to mucosa border (DIM), the extent of epithelial downgrowth (ED), the attachment level (AL). the length of connective tissue contact (CTC) and the distance of the first coronal alveolar bone contact from the implant top (DIB) were measured at the mesial and distal aspects. Means+standard deviations for submerged and nonsubmerged implants were calculated, with the dog being the unit of measure. No statistically significant differences between submerged and nonsubmerged implants here found for DIM, CTC and DIB. However, significant differences were observed for ED and AL. This study in beagle dogs indicates that the apical extension of the peri-implant epithelium is significantly greater and the attachment level significantly lower adjacent to submerged implants with second-stage transmucosal abutments than in nonsubmerged, one-stage implants.