The four principal metabolites of cyclooxygenase (CO) were examined during the progression of experimental periodontitis in the rhesus monkey Macaca mulatta. Thirty-two monkeys were divided in four disease-matched groups. Three groups were treated with flurbiprofen, a potent CO inhibitor, at either 0.027, 0.27 or 7.1 mg/kg/day delivered systemically by a subcutaneously-implanted osmotic mini-pump. We have previously described the findings indicating that flurbiprofen treatment significantly retarded clinical attachment loss (ALOSS), redness and radiographic bone loss (BLOSS). This investigation focuses on the changes in CO metabolites which occur during disease progression of ligature-induced periodontitis and on the dose-response relationship of flurbiprofen, as it relates to disease inhibition and the suppression of ARA metabolites within the crevicular fluid (CF). In untreated animals there was a statistically significant 3-fold increase in CF levels of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) at 3 months, as compared to baseline, which positively correlated with increases in redness, bleeding, ALOSS and BLOSS. CF-PGE2 and TxB2 levels reached a 6-fold peak at 6 months and returned to baseline by 12 months. Flurbiprofen (Fb) prevented the 3-month rise in TxB2, but did not affect the increase in PGE2. At 6 months, Fb administration caused a dose-dependent inhibition of both PGE2 and TxB2. Probit analysis of the dose-response data revealed that the concentration of Fb which caused a 50% inhibition of CF-TxB2 level (the IC50 value for TxB2 synthesis) was approximately two logs lower than the IC50 value for PGE2 synthesis, i.e. TxA2-IC50 = 0.013 vs. PGE2-IC50 = 1.35 mg flurbiprofen/kg/d. The slopes of the PGE2 and TxB2 inhibition curves were identical, consistent with a similar mechanism or singular enzyme for the site of action of Fb inhibition of CO activity. However, the kinetics and sensitivity of Fb inhibition were significantly different for the CO activity responsible for TxB2 and PGE2 synthesis, perhaps due to different compartmentalization of CO within different cell types.

The effect of the nonsteroidal anti‐inflammatory drug flurbiprofen has been studied in the ligature‐induced and spontaneous periodontitis model in the rhesus monkey, Macaca mulatta. Twenty‐four adult monkeys with incipient periodontitis were divided into three disease‐matched groups. Two groups received flurbiprofen at dosages of either 0.27 mg/kg/d or 7.1 mg/kg/d delivered systemically via osmotic minipump. A split‐mouth approach was used, placing ligatures on one side and monitoring the progression of periodontitis at regular intervals for 6 months. Clinical measurements included standardized radiographs, Ramfjord attachment level determinations and assessments of redness, edema and bleeding on probing. There was a statistically significant inhibition of attachment loss (p < 0.05), gingival redness (p < 0.05) and bleeding on probing (p < 0.05) in ligatureinduced and spontaneous periodontitis in the flurbiprofen‐treated animals at 6 months. Eight of 8 ligated control monkeys lost significant attachment (mean loss of 1.06 mm/site). Only 3 of 15 flurbiprofen‐treated ligated monkeys lost any significant attachment, with an overall mean loss of 0.34 mm/site, which was significantly less than the control loss of 1.06 mm/site at p = 4.46 times 10‐3. The odds of a control ligated monkey undergoing significant attachment loss in 6 months are elevated 29.3‐fold, as compared to the flurbiprofen‐treated, cohort monkey group. Flurbiprofen treatment also significantly inhibited spontaneous attachment loss for 6 months as compared to control monkeys, at p < 0.05. These data provide further evidence for the central role of cyclooxygenase products in the progression of periodontal disease. The ability of flurbiprofen to inhibit periodontal attachment loss, even in the presence of gross plaque accumulation, has significant implications for the potential use of flurbiprofen as an adjunctive periodontal therapeutic modality.

This investigation focuses on the changes in the concentrations of cyclooxygenase (CO) products present within the crevicular fluid in naturally-progressing periodontitis in the beagle and the effects of various non-steroidal anti-inflammatory drugs (NSAIDs) on these metabolite levels and disease progression. Six groups of 5-6 beagles with periodontitis were followed for 6 months to determine the pretreatment rate of radiographic bone loss. At baseline, groups of animals were placed on soft chow to promote disease progression. Groups were treated with either placebo, three different formulations of systemic ibuprofen, systemic naproxen or topical flurbiprofen. During the 6-month treatment phase, crevicular fluid (CF) samples and radiographs were taken at regular intervals. Radioimmunoassay of CF samples from untreated animals demonstrated a steady increase in prostaglandin E2 (PGE2) over baseline values. At 1 month, CF-PGE2 levels increased 2-fold over baseline and, by 6 months, had reached a 5- to 6-fold elevation. Crevicular fluid thromboxane B2 (CF-TxB2) levels rapidly reached a 4- to 5-fold peak over baseline at 1 month and subsequently dropped to a 2-fold elevation for the remainder of the study. The rate of bone loss (BLOSS) in untreated animals increased 38% during the 6-month period, as compared to baseline pretreatment BLOSS rates. Overall, there was a significant depression in the CF levels of both PGE2 and TxB2 in all NSAID-treated groups. All NSAID treatments significantly retarded BLOSS, ranging from 21.0-36.9% of the control BLOSS rate. Furthermore, CO activation represents a major regulatory step in bone destruction and may thereby serve as an important site for pharmacological modulation.