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Subgingival plaque samples were obtained from 162 sites in 27 adult periodontitis patients and 162 sites in 27 healthy patients using a standardized lavage technique. The distribution of 10 different microbial morphotypes was determined by darkfield microscopy. The lavage technique selectively samples the loosely adherent plaque at the base of the periodontal pocket and not the tooth-associated, adherent plaque. This standardized technique permits quantitative comparisons of numerical density of morphotype composition at different sites, in addition to qualitative comparisons or relative proportions. There was a significant positive association between the numerical density of each morphotype within the non-adherent plaque and the number of sites at which the organism was detected in both healthy and diseased subjects. A previously undescribed darkfield morphotype, has been detected with this method. This morphotype, a small motile coccobacillus (S-MO-CB) has been found to be the numerically dominant species in both health and disease. This morphotype has been recovered in pure culture following passage through a 0.4 μ filter and includes organisms of the Wollinella and Campylobacter genus. Non-motile organisms comprised less than 1-2% of the sample from healthy and diseased sites. Motile forms, such as spirochetes, had a high frequency of detection in healthy individuals. Analysis of pooled plaque samples revealed that the prevalence of cocci and fusiforms was significantly elevated in patients with healthy periodontium, as compared to patients with adult periodontitis. In adult periodontitis patients, the frequency of occurrence of medium spirochetes, filaments and small nonmotile rods was significantly elevated in pooled plaque. Analysis of individual sites indicated that the proportion and numerical density of most morphotypes within the non-adherent plaque were not significantly different in disease as compared to health. Disease is characterized by an increased % of small spirochetes and fusiforms at each site. At diseased sites which harbor small spirochetes, the numerical density is elevated four-fold, as compared to healthy sites which have small spirochetes. The numerical density of other morphotypes is not significantly different comparing healthy sites to diseased sites. Thus, the increase in the % of small spirochetes in disease in due to a site-localized four-fold increase in numerical density within the non-adherent plaque. [ABSTRACT FROM AUTHOR]

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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 m 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. The topical application of flurbiprofen was as effective in depressing CF levels of PGE2 and TxB2 as systemic or sustained release formulations of other NSAIDs. The data further substantiate the concept that much of the BLOSS that occurs in periodontal disease is mediated by products of the cyclooxygenase pathway. Further- more, CO activation represents a major regulatory step in bone destruction and may thereby serve as an important site for pharmacological modulation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The effect of the nonsteroidal anti-inflammatory drug flurbiprofen has been studied in the ligature-induced and spontaneous peridontitis model in the rehsus monkey, Macaca mulatta. Twenty -four adult monkeys with incipient peridontits were divided into three disease-matched groups. Two groups received flurbioprofen at dosages of either 0.27 mg/kg/d or 7.1 mg/kg/d delivered systimatically via osmotci minipump. A split-mouth approach was used, placing lignatures on one side and monitoring the progression of periodontitis at regular interval for 6 months. Clinical measurements included standardized radiographs, Ramfjord attachment level determination 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 ligature-induced and spontaneous peridontits in the flurbiprofen-treated animals at 6 months. Eight of 8 ligated control monkeys losts 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 × 10-3. The odds of a control ligated monkey undergoing 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<0.005 . These data provide further evidence for the central role of cylcooxygenase product in the progression of periodontal disease. The ability of flurbiprofen to inhibit periodontal attachment loss, even in the presence of loss plaque accumulation, has significant implications for the potential use of flurbiprofen as an adjunctive periodontal therapeutic modality. [ABSTRACT FROM AUTHOR]

Longitudinal data were collected over a period of at least 18 months and up to 3 years on 41 adult periodontitis patients (AAP Type III and IV). Rainfjord attachment level measurements and sampling of crevicular fluid (CP) at each tooth were repeated every 3 months. A mean full mouth CF prostaglandin E2 (MCF-PGE) value was determined for each patient at each visit. The three-mouth monitoring was continued until a single site demonstrated a statistically and clinically significant attachment loss (ALOSS) episode. Results indicated that in ALOSS patients the MCF-PGE was significantly elevated at the ALOSS visit as compared to previous levels. Furthermore, the sites which had the ALOSS had elevated levels as compared to the contralateral no ALOSS control sites (305.6±56.5 vs. 65.7 ± 6.89 ng/ml, mean±SEM). One month following treatment the CF-PGE level dropped to 16.9± 3.4 ng/ml at the ALOSS sites. Since the MCF-PGE level increases preceding the attachment loss episode, reaches a maximum at the sites which actually undergo ALOSS, and subsides following treatment, the possibility of using the MCF-PGE level to predict an oncoming future ALOSS episode was examined. The ALOSS patients had a MCF-PGE level of 113.4±9.0 ng/ml 6 months prior to the ALOSS episode, which was significantly higher than the no ALOSS patients' MCF-PGE level of 50.1±7.1. Analysis of MCF-PGE levels as a screening test indicate that this measurement has a high degree of sensitivity, specificity, and a predictive value of 0.92 0.95. Thus, this method has significant merit as a diagnostic tool to determine if a patient is in a state of remission or about to undergo an attachment loss episode. [ABSTRACT FROM AUTHOR]

The measurement of crevicular fluid PGF (CF-PGE) as an indicator of periodontal disease status was investigated. The association between CF-PGE levels and the PGE content of the adjacent periodontal tissues was found to be highly significant (P = 5.3 × 10). The high correlation (r = 0.925) between the log CF-PGE level and the tissue PGE concentration indicates that CF levels can be used to reliably predict tissue levels. The CF-PGE measurements at each periodontal site were found to be highly reproducible. Samples from adult and juvenile periodontitis patients demonstrated that the mean CF-PGE levels were correlated with disease severity, as determined by mean attachment loss. The mean CF-PGE level in juvenile periodontitis patients was almost three-fold higher than that present in adult periodontitis (144.0 ± 28.0 ng/ml vs 57.5± 8.7 ng/ml, mean±S.E., significant at P = 0.002). The use of CF-PGE concentrations as an indicator of disease activity (i.e. longitudinal attachment loss) cannot be demonstrated by this cross-sectional study. However, the CF-PGE measurement has been demonstrated to be a non-invasive, sensitive, reproducible, and reliable reflection of tissue levels of PGE2. The association of increasing levels of CF-PGE with increased severity and aggressiveness of disease is consistent with PGE as an inflammatory mediator of tissue destruction. [ABSTRACT FROM AUTHOR]

Study Objective: Although data from the Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) 1-4 trials have shown a similar postoperative bleeding risk between rivaroxban and enoxaparin in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA), anecdotal observations from local institutions have suggested that postoperative bleeding rates seemed higher in patients who received rivaroxaban than those reported in the RECORD trials. Thus, the objective of this pilot study was to assess postoperative bleeding events observed in clinical practice in patients receiving rivaroxaban after undergoing THA and TKA and to compare their results with those published in the RECORD trials., Design: Retrospective cohort study with a comparator group of patients from the RECORD 1-4 trials., Setting: Two institutions within a regional health care system., Patients: Four hundred forty adults who received at least one dose of rivaroxaban 10 mg daily after undergoing THA or TKA in the two institutions between August 2011 and October 2013 (cohort group), and 6183 patients who received rivaroxaban in the RECORD 1-4 trials (comparator group)., Measurements and Main Results: Postoperative bleeding was assessed in the cohort patients versus the patients in the RECORD trials. The primary outcome, occurrence of any postoperative bleeding, was a composite of major and clinically relevant nonmajor bleeding as defined in the RECORD trials. Any postoperative bleeding occurred in 6.8% of the cohort patients versus 3.2% of the RECORD trial patients (p<0.0001); 1.4% of the cohort patients versus 0.38% of the RECORD trial patients suffered a major bleed (p=0.013). Within defined major bleeding, bleeding leading to reoperation and clinically overt extrasurgical site bleeding resulting in either a hemoglobin level decrease of at least 2 g/dl or transfusion of 2 units or greater of packed red blood cells were reported in 0.68% versus 0.19% (p=0.073) and 0.68% versus 0.13% (p=0.032), respectively, of the cohort patients versus the RECORD trial patients., Conclusion: Overall, any postoperative bleeding in the cohort patients occurred significantly more frequently than that observed in the RECORD trial patients. The major bleeding rate was also significantly higher in the cohort patients, influenced by higher rates of bleeding leading to reoperation and clinically overt extrasurgical site bleeding resulting in either a hemoglobin decrease of at least 2 g/dl or transfusion of two units or greater of packed red blood cells. These findings from our pilot study are thought provoking and, thus, invite further investigation., (© 2015 Pharmacotherapy Publications, Inc.)

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.