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R Gordon

Publications and source records attributed to R Gordon.

At least 55 records · Page 3Linked to original sources
PubMed1999

Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles.

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1998

Long-term prognostic value of exercise echocardiography compared with exercise 201Tl, ECG, and clinical variables in patients evaluated for coronary artery disease.

BACKGROUND: The accuracy of exercise echocardiography and 201Tl single photon emission computed tomography (SPECT) is similar in the diagnosis of coronary artery disease (CAD). However, comparative data on long-term prognosis are lacking. METHODS AND RESULTS: Clinical variables and exercise, echocardiographic, and 201Tl tomographic parameters were studied in 248 patients (age, 56+/-12 years [mean+/-SD]; 189 men) who underwent simultaneous treadmill exercise 201Tl SPECT and echocardiography. Follow-up was obtained in 225 patients (91%) at a mean of 3.7+/-2.0 years. A total of 64 cardiac events occurred. With the use of stepwise logistic regression, 4 models simulating clinical stress testing scenarios were evaluated in the prediction of all cardiac events, ischemic events, and/or cardiac death. The best clinical models were exercise echocardiography with exercise ECG and exercise 201Tl SPECT with exercise ECG. Both models were comparable in the prediction of cardiac events. For the exercise echocardiography model, exercise wall motion score index and induction of ischemia were the strongest predictors of events with ORs of 2.63 per unit increment (95% CI, 1. 34 to 5.17; P=0.005) and 4.1 (95% CI, 1.32 to 12.79; P=0.015), respectively. For the model with exercise 201Tl SPECT, the strongest predictor was ischemic perfusion defect (OR, 4.93; 95% CI, 1.72 to 14.08; P=0.003). The absence of ST changes during exercise decreased the risk of events. For the prediction of ischemic events and/or cardiac death, echocardiographic and 201Tl parameters were the only predictive variables. CONCLUSIONS: In patients evaluated for CAD, exercise echocardiography and 201Tl combined with ECG variables provide comparable prognostic information and can be used interchangeably for risk stratification.

Adult↗
PubMed1998

2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: selective and orally active cyclooxygenase-2 inhibitors.

A series of novel 2-pyridinyl-3-(4-methylsulfonyl)phenylpyridines has been synthesized and evaluated with respect to their ability to inhibit the isozymes of cyclooxygenase, COX-1, and COX-2. Optimum COX-2 activity is observed by introduction of a substituent at C5 of the central pyridine. 5- Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine 33 was identified as the optimum compound in this series.

Administration, Oral↗
PubMed1998

Control of cytoskeletal architecture by the src-suppressed C kinase substrate, SSeCKS.

Activation of protein kinase C (PKC) in many cell types results in cytoskeletal reorganization associated with cell proliferation. We previously described a new cell cycle-regulated myristylated PKC substrate, SSeCKS (pronounced essex), that interacts with the actin cytoskeleton [Lin et al., 1995, 1996]. SSeCKS shares significant homology with Gravin, which encodes kinase scaffolding functions for PKC and PKA [Nauert et al., 1997]. This article describes the cellular effects of ectopically expressing SSeCKS in untransformed NIH3T3 fibroblasts. Because the constitutive overexpression of SSeCKS is toxic [Lin et al., 1995], we developed cell lines with tetracycline (tet)-regulated SSeCKS expression. The induction of SSeCKS (removal of tet) caused significant cell flattening and the elaboration of an SSeCKS-associated cortical cytoskeletal matrix resistant to Triton X-100 extraction. Flattened cells were growth-arrested and marked by the formation of cellular projections and the temporary loss of actin stress fibers and vinculin-associated adhesion plaques. SSeCKS overexpression did not affect steady-state levels of actin, vinculin, or focal adhesion kinase (FAK) but did increase integrin-independent FAK tyrosine phosphorylation. Stress fiber loss was coincident with induced SSeCKS expression, strongly suggesting a direct effect. Cytochalasin, and to a lesser extent nocodazole, inhibited SSeCKS-induced cell flattening, however, only cytochalasin affected the shape of pre-flattened cells, suggesting a greater dependence on microfilaments, rather than microtubules. By contrast, only nocodazole caused retraction of the filopodia-like processes. These data indicate a role for SSeCKS in modulating both cytoskeletal and signaling pathways. Thus, we propose to expand SSeCKS scaffolding functions to include the ability to control actin-based cytoskeletal architecture, as well as mitogenic signal pathways.

3T3 Cells↗
PubMed1998

Combining various projection access schemes with the algebraic reconstruction technique for low-contrast detection in computed tomography.

We separately applied three different projection access orders (the multilevel scheme (MLS), the sequence access scheme (SAS) and the random permutation scheme (RPS)) to the algebraic reconstruction technique (ART) in an attempt to improve low-contrast object detection in computed tomography (CT). We used both simulated (from various numbers of projections of low-contrast and contrast detail phantoms) and actual data (from megavoltage portal CT) during our study. When coupled with ART, SAS and RPS led to poor low-contrast detection and required multiple iterations for convergence. In contrast, one-iteration MLS yielded the most uniform reconstructions with the highest contrast-to-noise ratios. Therefore, MLS-ART provides the highest dose efficiency of all current reconstruction techniques for imaging low-contrast objects from a small number of projections.

Algorithms↗
PubMed1998

Risk perceptions of offshore workers on UK oil and gas platforms.

Knowledge of the workforce's risk perceptions and attitudes to safety is necessary for the development of a safety culture, where each person accepts responsibility for working safely. The ACSNI Human Factors report stresses the importance of assessing workforce perceptions of risk to achieve a proper safety culture. Risk perception research has been criticized for insufficient analysis of the causal relationships between risk factors and perceived risk. The present study reports some of the factors which predicted risk perception in a sample of 622 employees from six UKCS offshore oil installations who completed a 15-section questionnaire. This paper focuses on the accuracy of workers' risk perceptions and what underlying factors predict the perception of personal risk from both major and minor hazards.

Accidents, Occupational↗
PubMed1998

Neotropical echinococcosis in Suriname: Echinococcus oligarthrus in the orbit and Echinococcus vogeli in the abdomen.

This paper reports two cases of neotropical echinococcosis caused by Echinococcus oligarthrus and E. vogeli, neither of which has been reported from Suriname. Case 1, a six-year-old boy, presented a 15 x 25 mm retro-ocular cystic tumor (observed by ultrasound, computed tomography scan, and magnetic resonance imaging) causing exophthalmia, chemosis, palpebral ptosis, and blindness of the left eye. Of two tentative diagnoses, Echinococcus cyst or dermoid tumor, the former was shown to be correct at surgery when a clear liquid and detached protoscoleces were aspirated. Rostellar hooks of the protoscolex were characteristic of E. oligarthrus. Case 2, a 41-year-old man, had polycystic masses excised from the liver and abdomen. A presurgery diagnosis of E. vogeli infection was made due to calcifications seen in the lesions, positive serology, residence of the patient in the tropical forest, and later by the size and shape of rostellar hooks. The presence of these two parasites in one of the former Guianas is not surprising; both species are endemic in tropical forest in Central and South America wherever people have not exterminated wild canids, especially the bush dog, (Speothos venaticus), and felids (wild cats of several species), along with pacas, agoutis, and other rodents that serve as intermediate host of these two cestodes. Eighty-six cases of polycystic echinococcosis are known in people from 11 countries from Nicaragua to Argentina: 32 due to E. vogeli, three to E. oligarthrus, and 51 for which determination of the species was not possible because the hooks of the protoscolex were not found or described. Research to elucidate aspects of transmission of E. vogeli and E. oligarthrus is of practical importance for defining measures for preventing the severe and frequently fatal illnesses caused by these two cestodes.

Abdomen↗
PubMed1998

Morphometric and electron-microscopic analyses of the effects of gonadotropin-releasing hormone agonists on uterine leiomyomas.

OBJECTIVE: Reports on the histologic effects of gonadotropin-releasing hormone agonists on uterine leiomyomas provide conflicting results. Most previous studies used qualitative methods of analysis. Using quantitative and semiquantitative stereologic methods of analysis, we assessed volume density of hyalinized areas, cell density, nuclear volume, and cytoplasmic cross-sectional areas of smooth muscle cells in histologic sections and also measured diameters of collagen fibrils in electron micrographs of uterine leiomyomas. DESIGN: Thirty leiomyomas from patients treated with gonadotropin-releasing hormone agonists (10 different patient samples), age-matched control patients (10 different patient samples), and postmenopausal women (10 different patient samples) were used. Hyalinization was assessed using a microscope with a projection head and affixed morphometric grid. Cell size and density were evaluated using a video-based, computerized system attached to the microscope, for which morphometric ad hoc programs were written. Diameters of collagen fibrils were measured from electron micrographs. SETTING: The study was conducted in the Department of Pathology, Mount Sinai Medical Center, New York, NY. PATIENTS: A total of 30 patient samples were studied, with three groups comprising 10 samples each, including patients treated with gonadotropin-releasing hormone agonists, age-matched control patients, and postmenopausal women. RESULTS: Myomas from patients treated with gonadotropin-releasing hormone agonists exhibited more hyalinization, greater cell density, slightly smaller cell sizes, and larger collagen fibrils than those of age-matched control patients and postmenopausal women. CONCLUSIONS: Shrinkage after treatment with gonadotropin-releasing hormone agonists is attributed to smaller cell size and increased collagenization in myomas.

Adult↗
PubMed1998

Distinct inflammatory responses of adherent vascular lung neutrophils to pulmonary irritants.

The nature and the extent of the damage that occurs in the lung following exposure to pulmonary irritants vary with the pathogenic agent. In the present studies we determined if this was due to unique functional responses of adherent vascular neutrophils to different irritants. Because of their location within the lung, these cells may be more relevant than circulating neutrophils to the pathophysiology of irritant-induced lung injury. For our studies we used two model irritants, ozone and endotoxin, which cause distinct pathologic effects in the lung. Treatment of rats with ozone resulted in a transient increase (2-fold) in the number of adherent vascular neutrophils in the lung which was maximum 2 hr after exposure and returned to control levels by 12 hr. In contrast, following endotoxin administration, 10-fold greater numbers of adherent neutrophils were recovered from the lung. Moreover, cell number remained elevated 3-fold for up to 48 hr. Unstimulated neutrophils isolated 2-12 hr after endotoxin treatment of rats produced 3 times more superoxide anion than cells from ozone-treated rats. Cells isolated 12-48 hr after endotoxin administration were also sensitized to produce more nitric oxide than cells from ozone-treated rats and to express inducible nitric oxide synthase protein. These data demonstrate that endotoxin and ozone induce distinct patterns of accumulation and functional changes in adherent vascular neutrophils in the lung which may contribute to different pathological processes observed following exposure to these pulmonary irritants.

Animals↗
PubMed1997

High resolution analysis of chromosome 3p alterations in cervical carcinoma.

Although loss of heterozygosity (LOH) for loci on chromosome 3p is a common event in cervical carcinoma (CC), the frequency and affected regions of 3p are inconsistent among studies. Here we report a comprehensive analysis of LOH on 3p in 66 primary tumors and 16 CC-derived cell lines using a high density of marker loci. Clonal LOH was found in over 70% of primary tumors, and the patterns of loss indicated four to five target regions, with 3p14 being the most frequent. The majority of tumors had complex patterns of allelic imbalance, with regions of subclonal and clonal losses often present in individual tumors. We exploited marker homozygosity in CC-derived cell lines as an indirect measure of LOH and identified four homozygous deletions (HDs) during this analysis at loci located within the 3p14.2 region to which the FHIT gene has been mapped recently. This led to a careful reevaluation of the LOH patterns in primary CCs, which showed apparent retention of heterozygosity for loci in this region indicative of the presence of several additional HDs. To our knowledge, this is the first report of HDs encompassing the FHIT gene region in primary tumor samples and underscores the usefulness of high resolution genetic analysis of tumor genomes in determining the chromosomal aberrations underlying the malignant progression of CC.

Alleles↗
PubMed1997

Endoscopic sclerotherapy compared with percutaneous transjugular intrahepatic portosystemic shunt after initial sclerotherapy in patients with acute variceal hemorrhage. A randomized, controlled trial.

BACKGROUND: Hemorrhage from esophageal varices remains a substantial management problem. Endoscopic sclerotherapy was preferred for more than a decade, but fluoroscopically placed intrahepatic portosystemic stents have recently been used with increasing frequency. OBJECTIVE: To compare sclerotherapy with transjugular intrahepatic portosystemic shunt (TIPS) in patients with bleeding from esophageal varices. DESIGN: Randomized, controlled clinical trial. SETTING: Three teaching hospitals. PATIENTS: 49 adults hospitalized with acute variceal hemorrhage from November 1991 to December 1995: 25 assigned to sclerotherapy and 24 assigned to TIPS. INTERVENTION: Patients assigned to repeated sclerotherapy had the procedure weekly. In those assigned to TIPS, an expandable mesh stent was fluoroscopically placed between an intrahepatic portal vein and an adjacent hepatic vein. MEASUREMENTS: Pretreatment measures included demographic and laboratory data. Postrandomization data included index hospitalization survival, duration of follow-up, successful obliteration of varices, rebleeding from varices, number of variceal rebleeding events, total days of hospitalization for variceal bleeding, blood transfusion requirements after randomization, prevalence of encephalopathy, and total health care costs. RESULTS: Mean follow-up (+/-SE) was 567 +/- 104 days in the sclerotherapy group and 575 +/- 109 days in the TIPS group. Varices were obliterated more reliably by TIPS than by sclerotherapy (P < 0.001). Patients having TIPS were significantly less likely to rebleed from esophageal varices than patients receiving sclerotherapy (3 of 24 compared with 12 of 25; P = 0.012). No other follow-up measures differed significantly between groups. A trend toward improved survival, which was not statistically significant, was noted in the TIPS group (hazard ratio, 0.53 [95% CI, 0.18 to 1.5]). CONCLUSIONS: In obliterating varices and reducing rebleeding events from esophageal varies, TIPS was more effective than sclerotherapy. However, TIPS did not decrease morbidity after randomization or improve health care costs. It seemed to produce better survival, but the increase in survival was not statistically significant.

Adult↗
PubMed1997

Synchronous lingual granular cell tumor and squamous carcinoma. A case report and review of the literature.

Granular cell tumor (GCT) is a benign lesion with a preference for subcutaneous sites. Marked pseudoepitheliomatous hyperplasia, seen in 10% of GCTs, might be misdiagnosed as squamous cell carcinoma (SCC), and GCT in the oral tissues has been referred to as a medical curiosity in the literature. We report the clinicopathologic, immunohistochemical, and ultrastructural findings in a case of coexistent SCC and GCT in the tongue. There is no evidence in this case that suggests malignant transition of the GCT to carcinoma. To the best of our knowledge, this is the first report of synchronous GCT and SCC in the oral cavity.

Adult↗
PubMed1997

B-cell deficiency does not abrogate development of cutaneous hyperplasia in mice inheriting the defective fibrillin-1 gene.

Tight-skin (TSK) mouse, the experimental model for scleroderma, develops cutaneous hyperplasia, cardiac hypertrophy, pulmonary emphysema and autoimmunity against scleroderma target autoantigens. The cutaneous hyperplasia is associated with the accumulation of microfibrils and elastic fibers in the middle and deep dermis. Fibrillin-1 (Fbn-1) is a major component of the 10-12 nm microfibrils found in the extracellular matrix. In this study we report the identification of a genetic marker in the Fbn-1 gene that can distinguish the mutant phenotype. TSK mice exhibit an unique polymorphism in the Fbn-1 gene. RNA analysis, PCR analysis and sequence determination of the mutant gene showed that the Fbn-1 gene polymorphism is due to intragenic duplication of a segment of the gene coding for 3.0 Kb of mRNA sequence (10 Kb of the genome). Histological analysis of skin samples from F1 progeny obtained by crossing TSK mice with JH-/-, RAG2-/- or vit/vit showed a significant correlation between the inheritance of the defective Fbn-1 gene and the development of cutaneous hyperplasia. Further, our results also show that in mice deficient in mature B cells inheriting the defective Fbn-1 gene, development of cutaneous hyperplasia is not abrogated. Thus, production of autoantibodies or the presence of mature B lymphocytes do not play an integral role in the pathogenesis of cutaneous hyperplasia.

Amino Acid Sequence↗
PubMed1997

Effect of temperature on the activities of glucose-6-phosphate dehydrogenase and hexokinase in entomopathogenic nematodes (Nematoda: Steinernematidae).

The kinetic properties of two metabolic enzymes, glucose-6-phosphate dehydrogenase and hexokinase, were studied in four strains of entomopathogenic nematodes that had been recycled for two years at various temperatures: Steinernema feltiae NF strain, Steinernema feltiae Umeå strain, Steinernema carpocapsae All strain, Steinernema riobravis TX strain. The recycling temperatures influenced the activities of glucose-6-phosphate dehydrogenase and hexokinase in an adaptive fashion in all the strains. At each assay temperature (5-35 degrees C), the maximum specific activity of both the enzymes was greater in the nematodes that had been recycled at lower temperatures than in those reared at higher temperatures. In three enzyme-nematode strain combinations, the lowest K(m) values measured at each assay temperature occurred in nematodes that had been recycled at the lower temperatures. However, the assay temperatures at which the minimum K(m) values occurred were > or = 15 degrees C. The capacities of these nematodes to adjust to different recycling temperatures is discussed in relation to the physiological mechanisms involved.

Animals↗
PubMed1997

Detection of breast cancer at a smaller size can reduce the likelihood of metastatic spread: a quantitative analysis.

RATIONALE AND OBJECTIVES: The authors extrapolated the lognormal relationship between size of tumor and probability of metastasis to include small tumors. METHODS: Extrapolation was performed by using linear weighted regression analysis techniques to estimate prediction intervals for the predicted probabilities. RESULTS: Tumors detected at 1 cm in diameter had a 7.31% probability of metastasis (95% prediction interval [PI], 4.36% to 11.6%). Tumors detected at 5 mm in diameter had a 1.23% probability of metastasis (95% PI, 0.45% to 3.0%). Tumors detected at 2 mm had a 0.049% probability of metastasis (95% PI, 0.00705% to 0.267%). CONCLUSION: This analysis shows a major reduction in metastasis probability when tumors are detected at small sizes. These results suggest that detection of very early tumors can substantially reduce the likelihood of metastatic spread.

Breast Neoplasms↗
PubMed1997

Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor.

1. DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furan one) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor. 2. In CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) with at least a 1,000 fold selectivity for COX-2 (IC50 = 41 +/- 14 nM) over COX-1 (IC50 > 50 microM). Indomethacin was a potent inhibitor of both COX-1 (IC50 = 18 +/- 3 nM) and COX-2 (IC50 = 26 +/- 6 nM) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX-1 mediated production of thromboxane B2 (TXB2) by Ca2+ ionophore-challenged human platelets (IC50 > 50 microM and 4.1 +/- 1.7 nM, respectively). 3. DFU caused a time-dependent inhibition of purified recombinant human COX-2 with a Ki, value of 140 +/- 68 microM for the initial reversible binding to enzyme and a kappa 2 value of 0.11 +/- 0.06 s-1 for the first order rate constant for formation of a tightly bound enzyme-inhibitor complex. Comparable values of 62 +/- 26 microM and 0.06 +/- 0.01 s-1, respectively, were obtained for indomethacin. The enzyme-inhibitor complex was found to have a 1:1 stoichiometry and to dissociate only very slowly (t1/2 = 1-3 h) with recovery of intact inhibitor and active enzyme. The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site. 4. Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50 = 63 +/- 5 microM at 0.1 microM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1. 5. DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50 = 0.28 +/- 0.04 microM) similar to indomethacin (IC50 = 0.68 +/- 0.17 microM). In contrast, DFU was at least 500 times less potent (IC50 > 97 microM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50 = 0.19 +/- 0.02 microM). 6. In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 microM), DFU inhibited COX-1 with an IC50 value of 13 +/- 2 microM as compared to 20 +/- 1 nM for indomethacin. CGP 28238, etodolac and SC-58125 were about 10 times more potent inhibitors of COX-1 than DFU. The order of potency of various inhibitors was diclofenac > indomethacin approximately naproxen > nimesulide approximately meloxicam approximately piroxicam > NS-398 approximately SC-57666 > SC-58125 > CGP 28238 approximately etodolac > L-745,337 > DFU. 7. DFU inhibited dose-dependently both the carrageenan-induced rat paw oedema (ED50 of 1.1 mg kg-1 vs 2.0 mg kg-1 for indomethacin) and hyperalgesia (ED50 of 0.95 mg kg-1 vs 1.5 mg kg-1 for indomethacin). The compound was also effective at reversing LPS-induced pyrexia in rats (ED50 = 0.76 mg kg-1 vs 1.1 mg kg-1 for indomethacin). 8. In a sensitive model in which 51Cr faecal excretion was used to assess the integrity of the gastrointestinal tract in rats, no significant effect was detected after oral administration of DFU (100 mg kg-1, b.i.d.) for 5 days, whereas chromium leakage was observed with lower doses of diclofenac (3 mg kg-1), meloxicam (3 mg kg-1) or etodolac (10-30 mg kg-1). A 5 day administration of DFU in squirrel monkeys (100 mg kg-1) did not affect chromium leakage in contrast to diclofenac (1 mg kg-1) or naproxen (5 mg kg-1). 9. The results indicate that COX-1 inhibitory effects can be detected for all selective COX-2 inhibitors tested by use of a sensitive assay at low substrate concentration. The novel inhibitor DFU shows the lowest inhibitory potency against COX-1, a consistent high selectivity of inhibition of COX-2 over COX-1 (>300 fold) with enzyme, whole cell and whole blood assays, with no detectable loss of integrity of the gastrointestinal tract at doses >200 fold higher than efficacious doses in models of inflammation, pyresis and hyperalgesia. These results provide further evidence that prostanoids derived from COX-1 activity are not important in acute inflammatory responses and that a high therapeutic index of anti-inflammatory effect to gastropathy can be achieved with a selective COX-2 inhibitor.

Administration, Oral↗
PubMed1997

Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells.

Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.

Adaptor Proteins, Signal Transducing↗