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  • 1
    ISSN: 1600-0765
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The four principal metabolites of cyclooxygenase (CO) were examined during the progression of experimental periodontitis in the rhesus monkey Macaca mulalla. 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 dosedependent inhibition of both PGE2 and TxB2. Probit analysis of the doseresponse 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.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1600-0765
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 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.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 32 (1976), S. 498-500 
    ISSN: 1420-9071
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 35 (1979), S. 515-515 
    ISSN: 1420-9071
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Lack of dietary ascorbic acid lowered plasma levels of ascorbic acid but failed to change levels of brain norepinephrine or dopamine.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Considerable evidence has demonstrated the importance of PGE2 synthesis in the pathogenesis of periodontal disease. Although various cyclooxygenase inhibitors have been known to block periodontal PGE2 synthesis and prevent disease progression in animal models, there are few reports comparing relative efficacies of various inhibitors of arachidonic acid (ARA) metabolism. We have developed a sensitivein vitro assay to measure PGE2 synthesis in periodontal tissues. The apparent IC50 values (i.e. the concentration of drug which causes 50% inhibition of maximum PGE2 synthesis) have been determined for a series of arachidonic acid analogues as well as competitive and non-competitive cyclooxygenase inhibitors. Periodontal tissue homogenates were incubated in the presence of3H-arachidonic acid for 45 min at 37°C. Inhibitors were tested at 10−10–10−4 M and at zero concentration to measure conversion of3H-arachidonate to3H-PGE2. Log or half log dilutions of inhibitors were tested in triplicate for each assay. Radiolabeled PGE2 was extracted from homogenates, purified by reverse phase chromatography and quantitated by double antibody capture. RIA was performed on each homogenate to determine the amount of endogenous unlabeled PGE2 present in the sample to correct for antibody capture recovery. The apparent IC50 values were determined for each drug by averaging two or more replicate assays. Specific total enzymatic activity of periodontal tissue homogenates was typically 5–11 pg PGE2/min/mg tissue. The following series of compounds were tested and are listed in order of increasing IC50 values: α-tocopherol (3.3×10−9 M), ketoprofen (5.4×10−9 M), indomethacin (1.0×10−8 M), flurbiprofen (1.5×10−8 M), meclofenamate (1.5×10−6 M), naproxen (2.5×10−6 M), docosahexaenoic acid (1.0×10−5 M), eicosapentaenoic acid (1.5×10−5 M), and ibuprofen (1.5×10−5 M). These data will enable the rational design of pharmacological formulations to inhibit periodontal tissue PGE2 synthesis and resultant inflammation, attachment loss and bone resorption.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1998
    Keywords: Bone scan ; Child abuse ; Costovertebral fracture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Many patterns of injury have been described in the child abuse syndrome. Until recently, all the bone manifestations of this syndrome have been diagnosed radiologically. Four cases of multiple costovertebral fracture diagnosed by bone scan are described and their etiology discussed. The use of bone scanning in identifying fractures which previously would have been missed is advocated.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1569-8041
    Keywords: breast cancer ; cardiotoxicity ; cyclophosphamide ; epirubicin ; high dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: To prospectively evaluate the long term cardiac effects of high-dose epirubicin and cyclophosphamide given to women with early stage, poor prognosis breast cancer. Patients and methods: Women with stage 2 breast cancer and 10+ nodes or 4+ nodes and estrogen receptor negative tumor, or stage 3 breast cancer received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 gm/m2 with peripheral blood progenitor cell and filgrastim support. Treatment was given every 28 days (n = 79) or 21 days (n = 20). Fifty patients received radiotherapy to the chest wall or breast, 25 of to the left side. Patients were assessed clinically regularly during chemotherapy and at least three times yearly after completion of treatment. Cardiac left ventricular ejection fraction (LVEF) was assessed by radionuclide scan before therapy, after each cycle of chemotherapy, three months and six months after completion of chemotherapy, and yearly thereafter until relapse. Results: Ninety-nine women were treated, and 92 completed all three cycles of chemotherapy. The median age was 43 years (range 24 to 60 years). All patients were included in this analysis. The median relapse-free survival was 39 months (11 to 68 months). There was a significant fall in LVEF during chemotherapy. In general, there was no further deterioration in cardiac function from the third month after cessation of treatment, however there was substantial variation between individuals. 35 patients had at least one LVEF measure less than normal (〈50%), but the LVEF returned to normal in 20 of these with further follow-up. Cardiac dysfunction was not increased in women who received radiotherapy and was not different between cohorts given chemotherapy every three or every four weeks. One patient died of acute myocardial necrosis following the third cycle of chemotherapy. Two patients developed clinical evidence of cardiac failure, and another had radiological signs but was asymptomatic. One woman died of progressive cardiac failure, one recovered clinically but also developed recurrent breast cancer, while the third recovered after commencement of medical therapy. Conclusions: During follow-up after high-dose epirubicin and cyclophosphamide as delivered in this study, the LVEF fell to below normal in approximately one third of patients. However, in over half of these patients the LVEF subsequently recovered to the normal range, and the incidence of clinically evident chronic cardiac failure was low. Further follow-up is required to assess the long- term safety. A randomized comparison with standard-dose anthracycline-based chemotherapy is needed to determine whether this regimen is associated with an increased risk of clinical cardiac toxicity.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1569-8041
    Keywords: cyclophosphamide ; dose-escalation ; epirubicin ; filgrastim ; G-CSF ; non-Hodgkin's lymphoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL). Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages. Results: The MTD in stage I was epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m2, cyclophosphamide 1500 mg/m2, vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir 〈0.5 × 109/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (〈25 × 109/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity. Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.
    Type of Medium: Electronic Resource
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