Search PubMed⌕ Search

Biomedical subjects

R R Harris

Publications and source records attributed to R R Harris.

At least 37 records · Page 2Linked to original sources
PubMed1992

Synthesis, chemical, and biological properties of vinylogous hydroxamic acids: dual inhibitors of 5-lipoxygenase and IL-1 biosynthesis.

Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.

Animals↗
PubMed1992

Novel 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols with topical antiinflammatory activity.

The synthesis, biological evaluation, and structure-activity relationships of a series of 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols are described. These compounds show potent dose-dependent topical antiinflammatory activity in murine models of skin inflammation. This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin. These compounds were examined for their ability to inhibit the oxidative metabolism of arachidonic acid; they specifically inhibit the formation of prostacyclins in mouse macrophages. To study the effects of structure on the in vivo activity, three general features of the molecules were varied: the position of attachment of the pyridine nucleus (A), the second aromatic residue (B), and the nitrogen base on the ethanol chain (C). 1-[4-(4-Pyridyl)phenyl]-1-(4-fluorophenyl)-2- imidazolylethanol (2a, DuP 983) shows a very attractive profile of antiinflammatory activity and has been selected for clinical evaluation as a topical antiinflammatory agent.

Administration, Topical↗
PubMed1991

Phospholipase A2 (PLA2) activity in bovine pulmonary artery endothelial cells.

We have investigated the role of recombinant human interleukin-1 beta (rIL-1 beta) and recombinant human tumor necrosis factor alpha (rTNF-alpha) on PLA2 activity, protein synthesis and eicosanoid production in bovine pulmonary artery endothelial cells. Cellular PLA2 activity increased 4-fold and production of PGE2 increased 3-fold at 1-2 hrs in the presence of 10 units/ml rIL-1 beta. PLA2 activity increased 3-fold at 30 min and PGE2 production increased 2-fold with 5 x 10(-9) M rTNF-alpha. The data show that endothelial cells respond more rapidly to rIL-1 beta (2-6 hr) and rTNF-alpha (30 min) than do chondrocytes and synovial cells (6-16 hrs), suggesting endothelial cells may play a primary role in initiating the inflammatory response.

Animals↗
PubMed1990

2-substituted-1-naphthols as potent 5-lipoxygenase inhibitors with topical antiinflammatory activity.

The synthesis, biological evaluation, and structure-activity relationships of a series of 1-naphthols bearing carbon substituents at the 2-position are described. These compounds are potent inhibitors of the 5-lipoxygenase from RBL-1 cells and also inhibit bovine seminal vesicle cyclooxygenase. Structure-activity relationships for these two enzymes are different, implying specific enzyme inhibition rather than a nonspecific antioxidant effect. 2-(Aryl-methyl)-1-naphthols are among the most potent 5-lipoxygenase inhibitors reported (IC50 values generally 0.01-0.2 microM) and show excellent antiinflammatory potency in the mouse arachidonic acid ear edema model. To study the effects of structure on in vitro and in vivo activity, four general features of the molecules were varied: the 2-substituent, the 1-hydroxyl group, substitution on the naphthalene rings, and the 1,2-disubstituted naphthalene unit itself. 2-Benzyl-1-naphthol (5a, DuP 654) shows a very attractive profile of topical antiinflammatory activity and is currently in clinical trials as a topically applied antipsoriatic agent.

Animals↗
PubMed1990

Cellular and biochemical characterization of the anti-inflammatory effects of DuP 654 in the arachidonic acid murine skin inflammation model.

The possible utility of DuP 654, a potent 5-lipoxygenase inhibitor, for treating human inflammatory skin disease was investigated in murine skin treated with 1.0 mg arachidonic acid (AA). When DuP 654 was applied to murine skin treated with AA, it inhibited the resulting inflammation and influx of cells. High performance liquid chromatography and radioimmunoassay analysis of lipid extracts from AA-treated ears indicated that the influx of polymorphonuclear leukocytes (PMN) was temporally preceded by an appearance of significant amounts of 5-HETE (6.7 +/- 1.4 ng/ear) and Leukotriene B4 LTB4 0.92 +/- 0.2 ng/ear) when compared with extracts of untreated ears (5-HETE, 02 +/- 0.3 ng/ear; LTB4, less than 0.1 ng/ear). The levels of the 5-lipoxygenase products were reduced by treatment with 10 micrograms/ear DUP 654. Lipid extracts from AA-treated ears contain chemotactic activity for human PMN and this chemotactic activity in the AA-treated ears could be reduced but not eliminated by immunosorption with anti-LTB4 antibodies coupled to protein A-agarose. The appearance of the chemotactic activity was inhibited by DuP 654. Taken together, these data suggest that DuP 654 may have utility in human inflammatory skin disease.

Animals↗
PubMed1989

Effects of recombinant interleukin-1 beta on phospholipase A2 activity, phospholipase A2 mRNA levels, and eicosanoid formation in rabbit chondrocytes.

We have investigated the effects of recombinant interleukin-1 beta (rIL-1 beta) on phospholipase A2 activity (PLA2), PLA2 messenger RNA levels, and eicosanoid production in rabbit chondrocytes. Phospholipase A2 activity increased 5 fold with exposure to 1.6 x 10(-11) M rIL-1 beta for 20 hours. An mRNA specific for an extracellular PLA2 was detected by RNA blot hybridization after treatment of the cells with rIL-1 beta. Hydroxylated derivatives of arachidonic acid, including prostaglandins, leukotriene B4, 5-hydroxyeicosa 6E, 8Z, 11Z, 14Z-tetraenoic acid, 12-hydroxyeicosa 5Z, 8Z, 10E, 14Z-tetraenoic acid and 15-hydroxyeicosa 5Z, 8Z, 11Z, 13E-tetraenoic acid increased in cells after rIL-1 beta treatment.

Animals↗
PubMed1989

Topical anti-inflammatory activity of DuP 654, a 2-substituted 1-naphthol.

Recent work suggests that one of the common biochemical characteristics of skin inflammatory diseases such as psoriasis is altered arachidonic acid metabolism with elevated levels of prostaglandins and leukotrienes. DuP 654, a 2-substituted 1-naphthol, is an exceptionally potent inhibitor of 5-lipoxygenase. DuP 654 was tested in various models of skin inflammation and was found to be potent at inhibiting edema induced by the topical application of arachidonic acid, tetradecanoyl phorbol acetate or the calcium ionophore A23187. DuP 654 was also effective in a murine model of contact sensitivity. DuP 654 was effective at reducing the numbers of infiltrating polymorphonuclear leukocytes in AA and TPA induced edema. These data, taken together, suggest that DuP 654 may be effective in treating human skin diseases.

Administration, Topical↗
PubMed1986

Lipid thermotropic transitions in human stratum corneum.

The techniques of differential scanning calorimetry (DSC) and thermal perturbation infrared (IR) spectrometry were used to investigate thermal transitions in intact, fractionated, and lipid-extracted human stratum corneum. The DSC results show 3 major and one minor thermal transition in the range of 30-120 degrees C. Of particular interest to this study are 2 transitions seen near 65 degrees and 75 degrees C in intact stratum corneum and a stratum corneum membrane preparation, but absent from lipid-extracted samples. Results of IR spectrometry show that thermally induced spectral changes related to enhanced motion of the lipid acyl chains also occur in the region of about 60-80 degrees C. The combined DSC and IR results show that the thermal transitions near 65 degrees and 75 degrees C depend on water concentration in a manner identical to that seen for a variety of lipid-water systems. Taken together, these results suggest that thermal transitions occurring near 65 degrees and 85 degrees C involve increased acyl chain motion of stratum corneum lipids.

Calorimetry, Differential Scanning↗
PubMed1985

A noninvasive, in vivo technique to quantitatively measure water concentration of the stratum corneum using attenuated total-reflectance infrared spectroscopy.

In order to noninvasively measure water concentration in the stratum corneum, infrared spectra were obtained using an attenuated total-reflectance technique in conjunction with Fourier transform spectroscopy. A weak water-absorbance band near 2,100 cm-1 was detected in both in vivo and in vitro spectra. The significance of this band is that it occurs in a region of the mid-infrared where the stratum corneum and most topically applied substances show no absorbance. In vitro spectra obtained as a function of ambient relative humidity showed an increase in the absorbance near 2,100 cm-1 with increasing water concentration in the stratum corneum. The combined in vivo and in vitro results lead to a quantitative assessment of water concentration in the uppermost layers of the stratum corneum.

Animals↗
PubMed1984

Effects of the anti-inflammatory agents indomethacin, metiamide and acetylsalicylic acid on the induction of hyperplasia in hamster cheek-pouch epithelium and ear epidermis.

Previous studies have shown that agents such as indomethacin and hydrocortisone act to reduce the level of epidermal hyperplasia produced by various chemical, but little information is available about the effects of such anti-inflammatory agents on the induction of hyperplasia in oral mucosa. Hamster cheek-pouch epithelium and ear epidermis were treated with indomethacin, metiamide and acetylsalicylic acid prior to treatment with turpentine, podophyllin or TPA. The levels of hyperplasia induced were monitored by rates of epithelial glycolysis, protein synthesis and mitosis. The response of the metabolic assays to epinephrine was also examined. Alone, turpentine, podophyllin and TPA each caused a 3-5 fold increase in the metabolic assays and loss of the normal tissue response to epinephrine. Tissues pretreated with indomethacin showed significant reductions in the levels of hyperplasia produced and they retained a normal response to epinephrine. No reduction in hyperplasia was observed following pretreatment with acetylsalicylic acid, an alternative inhibitor or prostaglandin synthesis or with metiamide, a histamine blocker. The results indicate that the production of epithelial hyperplasia by turpentine, podophyllin and TPA can be inhibited by indomethacin.

Animals↗
PubMed1984

Fatty-acid metabolism in oral mucosal epithelium of the hamster.

Little is known about the role of lipid metabolism in oral mucosal epithelia, although lipids probably play significant roles in the barrier function and in the production of energy for the various epithelial biosynthetic activities. The metabolic fate of exogenously added 14C-labelled oleic acid in pure epithelial sheets from hamster cheek-pouch has been investigated. Significant amounts of the label from the fatty acid were found in phosphatidyl choline, sphingomyelin and triglyceride fractions. Lesser amounts were found in cholesterol, cholesterol ester, ceramide and phosphatidyl ethanolamine. Estimations of the amount of ATP produced by both glycolysis and by fatty-acid beta-oxidation indicated that the 2 activities were essentially equal, which is in contrast to that reported for the epidermis. The results suggest that the oral mucosal epithelium, like the epidermis, is an active lipid-metabolizing tissue.

Animals↗
PubMed1983

Effects of repeated treatment of hamster ear epidermis and cheek-pouch mucosa with 12-0-tetradecanoylphorbol-13-acetate.

The effects of repeated stimulation of hamster oral mucosa and epidermis with 12-0-tetradecanoylphorbol-13-acetate (TPA), were examined using in vitro assays of glycolysis and amino acid incorporation. The response of control and hyperplastic tissues to epinephrine and cAMP, and their rates of incorporation of histidine and leucine, were also examined. Repeated treatment with TPA in the concentration range of 1 X 10(-8) to 1 X 10(-5) M resulted in increased rates of glycolysis, amino acid incorporation and mitosis in both tissues. During the induction of hyperplasia, a loss of the normal epithelial response to epinephrine was observed at Day 8, suggesting re-establishment of mechanisms controlling homeostasis. Application of TPA resulted in a reduction in the amount of histidine incorporated relative to leucine.

Amino Acids↗
PubMed1982

A quantitative ultrastructural analysis of changes in hamster cheek-pouch epithelium treated with vitamin A.

The ultrastructural changes induced by the topical application of retinol acetate on hamster cheek pouch epithelium were evaluated using stereological analysis. Electron micrographs were prepared of the basal and superficial regions of the nucleated cell layer of the epithelium obtained from 3 treated and 3 control animals and examined at two levels of magnification. A total of 528 micrographs were analyzed using a coherent double lattice test system. Although the mean thickness of the nucleated cell layer did not change significantly after 10 days of treatment with retinol acetate the formation of keratinized squames was completely inhibited. This was paralleled by significant changes in the volume density of a number of organelles in both the basal and superficial strata. Rough endoplasmic reticulum increased significantly whereas filaments, which maintained a constant diameter of approximately 9 nm, keratohyalin granules and membrane-coating granules decreased in both strata. Desmosomes also showed a significant decrease in numerical area density in the treated tissues. In contrast, no changes were observed in the volume density of the Golgi apparatus, free ribosomes or mitochondria in the treated epithelium. It is concluded that this treatment provides an epithelium lacking all features of keratinization and may be a useful model for examining metabolic activities specifically associated with keratinization.

Animals↗
PubMed1982

The diurnal variation of epidermal metabolism.

In previous studies, the rates of epidermal glycolysis and amino acid incorporation were found to parallel rates of mitosis in both the hypoplasia associated with starvation and the hyperplasia produced by treatment with hexadecane. To examine whether similar changes in epidermal metabolism accompany the known diurnal variation in epidermal mitotic activity, the rates of glycolysis and incorporation of amino acids in epidermal sheets from skin samples at various times during a 24-hr period were assayed. These activities were found to parallel the diurnal variation of mitosis demonstrated by metaphase counts. Diurnal variation of metabolism in the suprabasal layers was investigated by examining the relative rates of incorporation of histidine and leucine: it was found that histidine showed a broader peak of activity than that seen for the other measured activities. When epidermal samples were prepared form tissue treated with hexadecane to induce hyperplasia, an increase in metabolic activity and decrease in the amplitude of diurnal variation was observed. The results indicate that the general metabolic activities of the epidermis follow a diurnal pattern similar to that found for mitosis.

Amino Acids↗