Faculty Bibliography

5% Amlexanox oral paste (Aphthasol) was studied in four vehicle-controlled, randomized, double-blind, parallel group, multicenter, clinical studies involving 1335 subjects who had 1 to 3 aphthous ulcers less than 48 hours old at enrollment. Subjects applied study pastes directly to ulcers four times a day until ulcers healed or for the duration of the study, whichever occurred first. Ulcer size was measured by the investigator and pain was evaluated by the subject; the primary determinant of efficacy was the percentage of subjects with complete healing of ulcers and complete resolution of ulcer pain. The vehicle had marginal beneficial effects as would be expected from a covering material, but statistical significance over no treatment was inconsistent. However, these studies, both individually and collectively, clearly demonstrated in a highly significant and consistent manner that in comparison to both Vehicle and No Treatment 5% Amlexanox oral paste accelerates the resolution of pain and healing of aphthous ulcers

The safety of 5% Amlexanox paste was demonstrated in the following clinical studies: vehicle-controlled safety and efficacy studies; dermal irritation and sensitization studies; single and multiple dose pharmacokinetic studies; and a 28-day in use safety study. Minimal adverse experiences were observed with the 991 subjects that were exposed to 5% Amlexanox paste. No significant irritation or sensitization was associated with 5% Amlexanox paste. Pharmacokinetic studies indicated that systemic levels of Amlexanox are most likely due to normal gastrointestinal absorption with only limited absorption directly through the ulcer. After a 100 mg dose of 5% Amlexanox paste the average maximum concentration of Amlexanox in the serum was 120 ng/ml, occurring 2.4 hours after application. The half-life for elimination of Amlexanox was 3.5 hours, and there was no evidence of accumulation with multiple applications. Overall, the data indicate that 5% Amlexanox paste (Aphthasol) is safe for the treatment of recurrent minor aphthous ulcers

Ketoprofen creams were evaluated for the treatment of periodontal disease in a placebo-controlled, double-blind study in the rhesus monkeys, Macaca mulatta. Two formulations containing ketoprofen (1%), with or without vitamin E, were evaluated against appropriate controls (8 monkeys per group). Two weeks prior to treatment, the animals received prophylaxis on only the left side of the mouth (spontaneous model). Selected teeth on the right side of the mouth were ligated (ligature model). The creams were administered to the gingiva once daily at a standard dose of 1.8 ml per monkey for 6 months. Clinical assessments were made 2 wk before initiation, at baseline and 1, 2, 3 and 6 months post-treatment. The clinical parameters included plaque formation, gingival redness, edema, bleeding on probing and Ramfjord Attachment Level measurements (RAL). Radiographs were taken at 2 wk before initiation, baseline and at 3 and 6 months post-treatment. Digital, subtraction radiography was used to measure vertical linear bone loss along the interproximal root surfaces of the left and right mandibular first molars. Gingival crevicular fluid (GCF) was collected for biochemical assays on PGE2, TxB2, LTB4, IL-1 beta and TNF alpha. There were no significant differences among groups with respect to gingival indices. Radiographic data demonstrated significant positive effects on bone activity in both groups treated with ketoprofen formulations with improvement over time in the ligature model (0.01 < or = p < or = 0.04). The placebo group exhibited bone loss of 1.96 +/- 0.48 and 1.40 +/- 0.56 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream showed an apparent bone gain of 0.28 +/- 0.41 and 0.78 +/- 0.47 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream containing vitamin E showed a mean bone loss of 0.41-0.48 mm per site at 3 months with improvement to an apparent bone gain of 0.31 +/- 0.44 mm per site at 6 months. The biochemical data demonstrated early and significant suppression of GCF-LTB4 by both ketoprofen formulations at 1 month, which preceded the significant suppression of GCF-PGE2 at 2 and 3 months in the ligature model (p < 0.003) and at 2 to 6 months in the spontaneous model (p < 0.02). We conclude that ketoprofen at 1% level in suitable topical vehicles can effectively inhibit GCF-LTB4 and GCF-PGE2 and positively alter alveolar bone activity in the ligature-induced model of periodontitis in the monkey

Ligature-induced periodontitis was monitored for 6 months in eight Macaca mulatta monkeys to examine clinical status, radiographic bone level, and crevicular fluid (CF) levels of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and leukotriene B4 (LTB4). A split-mouth design was used, with eight ligated teeth and eight contralateral nonligated teeth which develop soft-chow-promoted (spontaneous) disease. Ligated sites experienced an average attachment loss of 0.94 mm per site and linear bone loss of 0.88 mm per site, with spontaneous-periodontitis sites experiencing approximately half the loss of ligated sites. The CF mediator levels showed increased levels of PGE2 and TxB2 at the ligated sites, as compared with the spontaneous sites, with no significant contralateral differences in the IL-1 beta or LTB4 responses. The concentrations of LTB4 in CF reached an early threefold peak over the baseline level at 1 month. By 2 months there was a statistically significant threefold elevation in CF-PGE2 in the ligated sites and a twofold elevation in the spontaneous sites as compared to the baseline level (P = 0.041 and 0.008, respectively). The monocyte product IL-1 beta increased sharply at 2 months and returned to the baseline level by 6 months at both ligated and nonligated sites. Tumor necrosis factor alpha in CF was below the limit of detection at all sites throughout the experiment (i.e., < 2 ng/ml). The selective elevation of both PGE2 and TxB2 in ligated sites, compared with levels in spontaneous sites, in the presence of similar levels of LTB4 and IL-1 beta provides further evidence that these molecules regulate the magnitude of the tissue-destructive response in progressive periodontitis.

The effect of zinc sulfadiazine (ZnSD) and silver sulfadiazine (AgSD) on reducing plaque formation and gingivitis was studied in 12 beagle dogs over a 14-week period. 12 beagle dogs were scaled, root planed and pumiced to bring them to a similar level of gingival health, prior to placing them on a diet of Purina Dog Chow softened with canned gravy and molasses to promote the build-up of plaque and the initiation of gingivitis. At the end of 8 weeks, the dogs were determined to have substantial bacterial plaque accumulation and apparent gingivitis. Thereafter, 4 dogs were treated 2 x daily with topical applications of 3% zinc sulfadiazine; 4 dogs were treated with 2% silver sulfadiazine while 4 dogs were treated with placebo gel serving as control over a 14-week treatment period. By week 2, the zinc and silver sulfadiazine dogs showed a significant decrease in gingival index which was maintained throughout the study. Additionally, by week 2, the % of sites with bleeding was also seen to decrease significantly in the experimental groups. The plaque index remained consistent in all 3 groups until week 6 when the 2 experimental groups indicated significant decrease in plaque accumulation as compared to controls. Probing depths were also seen to decrease significantly in the experimental groups after 10 weeks of therapy. The mean stain index was similar in all 3 groups of dogs throughout the study. Data indicate that both zinc and silver sulfadiazine inhibit plaque formation and reduce existing gingivitis in beagle dogs

The effect of zinc sulfadiazine (ZnSD) and silver sulfadiazine (AgSD) on developing plaque formation and gingivitis was studied in 12 beagle dogs over a 14-week period. Plaque and gingival indices were used to measure plaque formation and gingivitis. During a 2-wk baseline period each dog was brought to optimal gingival health with prophylaxis and tooth brushing. Thereafter, 4 dogs were treated twice daily with topical application of 3.0% zinc sulfadiazine; 4 dogs were treated with 2.0% silver sulfadiazine while 4 dogs treated with placebo gel served as controls over a 12-wk treatment period. At wk 2 of treatment, all three groups of dogs showed an increase in plaque build-up on their teeth from baseline. By wk 6, plaque accumulation on the teeth was significantly less in dogs treated with either ZnSD or AgSD compared to control dogs. At wk 2 of treatment, gingival inflammation was increased from baseline in all three groups. Thereafter, over the course of the 12-wk treatment period, gingival inflammation in the ZnSD and the AgSD treated dogs was significantly less than the placebo treated dogs. The data indicate that both ZnSD and AgSD inhibit developing plaque formation in beagles. This significant inhibition of plaque formation was accompanied by a significant reduction in gingival inflammation