Biomedical subjects

D O Thueson

Publications and source records attributed to D O Thueson.

At least 19 recordsLinked to original sources

PubMed1998

The roles of pH and concentration in lactic acid-induced stimulation of epidermal turnover.

BACKGROUND: Alpha hydroxy acids such as lactic and glycolic acids (AHAs) accelerate epidermal turnover and exfoliate the stratum corneum. The roles of pH and concentration in these antiaging effects of AHAs is unclear, but a lower (more acidic) pH and higher concentration of acid are thought to be more effective. OBJECTIVE: To examine the effects on skin renewal rates of lactic acid 10% at pHs of 2.0, 3.0, and 4.0, and of 5%, 10% and 15% lactic acid at a pH of 3.0. METHODS: Twenty-six female subjects participated in the double-blind, randomized, placebo-controlled study. The dansyl chloride stain technique was used to measure epidermal renewal times. RESULTS: Both pH and concentration are critical in the lactic acid effect. At a fixed lactic acid concentration, the desquamative effect was highly pH dependent. At a fixed pH, the turnover rate of skin was concentration dependent. CONCLUSION: The desquamative and proliferation-stimulating effects of lactic acid are very pH and concentration dependent, suggesting the "free acid" concentration is the active moiety.

Adult↗

PubMed1994

Selective regulation of human neutrophil functions by the cell activation inhibitor CI-959.

The cell activation inhibitor CI-959 [5-methoxy-3-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzo[ b]thiophene-2- carboxamide, monosodium salt] was evaluated for its effects on human neutrophil functions. CI-959 inhibited spontaneous migration and chemotaxis toward N-formyl-methionyl-L-leucyl-L-phenylalanine (fMLP) with 50% inhibition (IC50) values of 3.6 and 3.1 microM, respectively. CI-959 also inhibited superoxide anion generation in response to C5a, fMLP, serum-opsonized zymosan (SOZ), concanavalin A (Con A), and calcium ionophore A23187 with IC50 values of 2.5, 4.7, 14.5, 5.4, and 14.8 microM, respectively. In comparison, CI-959 inhibited myeloperoxidase microM, respectively. In comparison, CI-959 inhibited myeloperoxidase release in response to C5a, fMLP, SOZ, and Con A with IC50 values of 11.6, 16.1, 7.5, and < 1.0 microM, respectively, while inhibiting the response to A23187 by only 5.5% at 100 microM. At concentrations up to 100 microM, CI-959 had no effect on the respiratory burst or degranulation in response to L-alpha-1,2-dioctanoylglycerol (DiC8) or phorbol 12-myristate 13-acetate (PMA). In addition, the compound inhibited leukotriene B4 release stimulated by fMLP and SOZ (IC50 values 4.0 and 2.5 microM, respectively), while having less activity against the A23187-stimulated response (IC50 > 100 microM). These results demonstrate that CI-959 inhibits cellular responses to stimuli that mobilize intracellular calcium. For cellular responses to inophore-mediated calcium influx, only oxygen radical production was inhibited by CI-959. CI-959 was further evaluated for its effects on neutrophil stimulus-response coupling. At 100 microM, CI-959 had no effect on human neutrophil phospholipase C or protein kinase C. CI-959 inhibited fMLP-stimulated intracellular calcium mobilization and calcium influx with IC50 values of 16.7 and 3.1 microM, respectively, and exhibited less potent calmodulin antagonist activity (IC50 = 90.5 microM). These results indicate that CI-959 may exert its stimulus- and response-specific inhibitory effects on neutrophil functions, in part, through inhibition of calcium-regulated signalling mechanisms.

Arachidonic Acid↗

PubMed1992

Novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic activity of a series of novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles are described. A number of the compounds inhibit the release of histamine from anti-IgE stimulated basophils obtained from allergic donors. Optimal inhibition is exhibited in benzothiophenes with a 3-alkoxy substituent in combination with a 5-methoxy, 6-methoxy, or a 5,6-dimethoxy group. Compound 13c (CI-959) also inhibited respiratory burst of human neutrophils and the release of mediators from anti-IgE-stimulated human chopped lung.

Antibodies, Anti-Idiotypic↗

PubMed1992

Differential regulation of human eosinophil, macrophage, and neutrophil functions by the allergic mediator release inhibitor CI-959.

The cell activation inhibitor CI-959 [5-methoxy-3-(1-methyl-ethoxy)-N-1H- tetrazol-5-ylbenzo[b]thiophene-2-carboxamide, monosodium salt] was evaluated for its effect on the activation of human eosinophils, macrophages, and neutrophils by the phagocytic stimulus serum-opsonized zymosan (SOZ). CI-959 inhibited the respiratory burst of eosinophils and neutrophils, measured as the generation of superoxide anion, with IC50s of 9.6 and 14.5 microM, respectively. In contrast, 100 microM CI-959 inhibited superoxide anion generation by human macrophages by only 22.7%. The compound exhibited a different inhibition profile for lysosomal enzyme release from these cells. At 100 microM, CI-959 inhibited the release of eosinophil peroxidase and macrophage N-acetyl-beta-D-glucosaminidase by only 19.5 and 25.6%, respectively. In contrast, CI-959 inhibited the release of the neutrophil primary granule enzyme myeloperoxidase with an IC50 of 7.5 microM, while inhibiting release of lysozyme from secondary granules by only 11.4% at 100 microM. These results demonstrate that oxygen radical generation and lysosomal enzyme release by human leukocyte populations are differentially regulated by CI-959.

Down-Regulation↗

PubMed1991

Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-949.

The allergic mediator release inhibitor Cl-949 [5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide, L-arginine salt] was evaluated for its effects on human neutrophil functions. Cl-949 (100 microM) inhibited spontaneous migration and chemotaxis toward f-met-leu-phe (FMLP) by 49.1% and 45.8%, respectively. At the same concentration, Cl-949 inhibited the phagocytosis of serum-opsonized zymosan (SOZ) by 39.0%. Cl-949 inhibited leukotriene B4 and thromboxane B2 release in response to SOZ with IC50s of 2.0 microM and 3.3 microM, while inhibiting the response to FMLP with IC50s of 1.7 and 2.0 microM. Cl-949 also inhibited myeloperoxidase release from primary lysosomal granules in response to the following stimuli with the respective IC50s (microM): C5a (40.3); FMLP (34.4): SOZ (21.4); concanavalin A (Con A) 3.9); and calcium ionophore A23187 (91.2). In contrast, Cl-949 inhibited lysozyme release from secondary granules in response to SOZ and Con A with IC50s of 99.3 and 56.1 microM, while inhibiting the response to C5a, FMLP, and A23187 by 41.2%, 52.4%, and 10.0%, respectively, at 100 microM. Cl-949 (100 microM) had no inhibitory effect against lysozyme release in response to L-alpha-1,2 dioctanoylglycerol (DiC8), or phorbol 12-myristate 13-acetate (PMA). Cl-949 inhibited superoxide anion generation stimulated by FMLP and Con A with IC50s of 33.9 and 25.8 microM, while inhibiting the response to C5a, SOZ, and A23187 by 36.6%, 24.8%, and 14.1% and having no effect on the response to DiC8 or PMA at 100 microM. These results demonstrate preferential inhibition of arachidonic acid metabolism and degranulation of primary lysosomal granules by Cl-949 with selectivity for stimuli which promote intracellular calcium mobilization or calcium influx.

Arachidonic Acid↗

PubMed1991

Novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic activity of a series of novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated human basophils. Optimal inhibition is exhibited in compounds with a 3-alkoxy, a 4-halo, and a 5-methyl, 5-methoxy, or 5-bromo on a thiophene-2-carboxamidotetrazole.

Basophils↗

PubMed1990

Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-949: mechanism of inhibitory activity.

CI-949 [5-methyl-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H- indole-2- carboxamide, L-arginine salt] inhibits human neutrophil activation in response to stimuli which promote calcium mobilization or calcium influx. This report further examines the effect of CI-949 on phosphoinositide-dependent stimulus-response coupling. At 100 microM, CI-949 had no inhibitory effect on human neutrophil phospholipase C or protein kinase C. In contrast, CI-949 inhibited FMLP-stimulated intracellular calcium mobilization with an IC50 of 8.4 microM. The compound was also a potent calmodulin antagonist, inhibiting calmodulin-dependent phosphodiesterase activity with an IC50 of 31.0 microM. The calmodulin antagonist activity of CI-949 was confirmed by fluorescence spectroscopy. These results demonstrate that CI-949 may function through inhibition of calcium- and calmodulin-dependent signal transduction processes.

Azoles↗

PubMed1990

Differential regulation of the activation of human eosinophils, macrophages, and neutrophils: effect of the allergic mediator release inhibitor CI-949.

The allergic mediator release inhibitor CI-949 [5-methoxy-3-(1- methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H-indole-2-carbox amide L-arginine salt] was evaluated for its effect on the activation of human eosinophils, macrophages, and neutrophils by the phagocytic stimulus serum-opsonized zymosan (SOZ). CI-949 inhibited the SOZ- stimulated respiratory burst of eosinophils, measured as the generation of superoxide anion, with an IC50 of 22.8 microM. At concentrations of 100 microM, CI-949 had no inhibitory effect against lysosomal enzyme release by these cells. At 100 microM, CI-949 had no inhibitory effect against release of eosinophil peroxidase while inhibiting release of the macrophage lysosomal enzyme N-acetyl-beta-D- glucosaminidase by only 11.7 percent. In contrast, CI-949 inhibited the release of the neutrophil primary granule enzyme myeloperoxidase inhibiting of 21.4 microM, while inhibiting release of lysozyme from lysosomal enzyme release from secondary granules with an IC50 of 99.3 microM. These results demonstrate that oxygen radical generation and lysosomal enzyme release by human eosinophils, macrophages and neutrophils are differentially regulated by CI-949. These results suggest that these inflammatory cells may have distinct stimulus-related coupling mechanisms.

Acetylglucosaminidase↗

PubMed1990

CI-949: a new, potential antiallergy compound inhibits antigen-induced allergic reactions in guinea-pigs in vitro and in vivo.

CI-949 (5-methoxy-3-(1-methyl-ethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide) effectively inhibited the release of histamine and the synthesis or release of immunoreactive sulfidopeptide leukotrienes C4-D4 and thromboxane B2 from antigen-challenged lung fragments of of actively sensitized guinea-pigs. The IC50s were 26.7 +/- 2.8 microM for histamine, 2.7 +/- 2.4 microM for leukotriene, and 3.0 +/- 1.8 microM for thromboxane. Drugs including ketotifen, cromolyn and nedocromil did not inhibit histamine release or did so only at high concentrations, and only cromolyn inhibited the synthesis or releases of the 2 eicosanoids. A dose of 50 mg/kg i.p. of CI-949 protected conscious, aerosol-allergen challenged guinea-pigs for at least 1 h and 100 mg/kg i.p. or per os protected for at least 2 h. These results, the comparisons to standard antiallergic drugs, and other data from experiments with human lung fragments and isolated peripheral leukocytes 1,2,3,4 suggest that CI-949 should be evaluated for clinical activity against allergic and inflammatory conditions in which histamine, sulfidopeptide leukotrienes, and/or thromboxane mediate symptoms.

Anaphylaxis↗

PubMed1990

Inhibition of histamine, leukotriene C4/D4, and thromboxane B2 release from human leukocytes and human chopped lung mast cells by the allergic mediator release inhibitor, CI-949.

The novel antiallergy compound, 5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H- indole-2- carboxamide, L-arginine salt (CI-949), inhibited mediator release from human basophilic leukocytes and from human chopped lung mast cells challenged with anti-IgE. In leukocytes, CI-949 was a more potent inhibitor of leukotriene C4/D4 and thromboxane B2 release (concentration of drug that inhibits mediator release by 50% [IC50] 0.5 and 0.1 mumol/L, respectively) than of histamine (IC50, 11.4 mumol/L) when anti-IgE was the challenging stimulus. In human lung, inhibition of release of all three mediators occurred at approximately equal concentrations (IC50s for histamine, 16.6 mumol/L; for leukotriene C4/D4, 7.1 mumol/L; and for thromboxane B2, 6.2 mumol/L). The inhibition of histamine release from basophils by CI-949 was further characterized using a variety of stimuli. Challenge with anti-IgE, histamine-releasing factor derived from lymphocytes, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, and concanavalin A revealed potent inhibition (IC50, 10 to 15 mumol/L). CI-949 was less potent versus calcium ionophore A23187, phorbol myristate acetate (12-o-tetradecanoylphorbol-13-acetate), and C5a (IC50s, 30, 54, and 60 mumol/L, respectively). These results suggest that diverse pathways of cell activation-excitation coupling exist for different stimuli in basophils. Furthermore, the activity and potency of CI-949 in inhibiting release of histamine, leukotrienes, and thromboxane from both human basophils and mast cells suggest that the compound will be effective clinically for indications in which these mediators are implicated, including asthma and allergic rhinitis.

Basophils↗

PubMed1990

CI-959, a new, potential antiallergic drug, inhibits mediator release from lung and contractions of human airways in vitro.

Many symptoms of the immediate allergic response can be attributed to the synthesis/release and subsequent actions of histamine and metabolic products of arachidonic acid oxidation. CI-959 [5-methoxy-3-(1-methylethoxy)-N-1H-tetrazole-5-yl-benzo(b) thiophene-2-carboxamide], a new, potential antiallergic drug, inhibited the release of histamine, immunoreactive sulfidopeptide leukotrienes C4, D4 and E4 and immunoreactive thromboxane B2 from immunologically activated guinea-pig and human lung cells in vitro. The IC50s of CI-959 using guinea-pig lung were: histamine, 0.8 +/- 1.4 microM; leukotriene, 0.7 +/- 1.6 microM and thromboxane, 9.6 +/- 3.3 microM. Using human lung the IC50s were: 2.3 +/- 1.3 microM for histamine; 0.3 +/- 5.1 microM for leukotriene, and 0.3 +/- 2.6 microM for thromboxane. CI-959 caused a concentration-dependent inhibition of anti-IgE-induced contractions of human bronchial muscle. Mean percent inhibitions were 45, 65 and 96 at 1, 3 and 10 microM, respectively. Cromolyn, 10 microM, inhibited bronchial contractions only 42%. The ability of CI-959 to inhibit these immunologically induced contractions indicates that the release of all mediators responsible for bronchoconstriction was effectively inhibited. These data suggest that CI-959 may be effective in preventing the development of symptoms directly related to inflammatory mediator release in a variety of allergic and inflammatory states.

Animals↗

PubMed1989

Effect of CI-949 and CI-959 on immune function and lymphoid organs in rats.

The immunotoxic properties of two experimental antiallergic drugs, CI-949 and CI-959, were investigated. Wistar rats were gavaged once (CI-949) or twice (CI-959) daily for 21 days with the drugs. Immunotoxicity was assessed using the enzyme-linked immunoabsorbant assay (ELISA) for humoral immunity, a delayed-type hypersensitivity (DTH) procedure for cell-mediated immunity, and natural killer cell (NKC) activity to evaluate spontaneous cytotoxicity. Ratios of body weight to spleen, thymus, liver and kidney weights were determined. Routine histopathology was performed on lymphoid tissue and other body organs. Although 100 mg/kg/day of CI-949 had some stimulating effect on antibody production and NKC cytotoxicity, no consistent immunomodulation was apparent. Except for a significant increase in liver weight at the 100 mg/kg dose of CI-949, no other toxic effects were observed. In contrast to CI-949, CI-959 significantly (P less than 0.05) suppressed antibody production at the 100 mg/kg dose and impaired the DTH reaction, although not significantly. Natural killer cell cytotoxicity was unaffected by 100 mg/kg CI-959. Decreased body weight and histopathological lesions were observed in the thymus and spleen of rats administered 100 mg/kg CI-959. These lesions ranged from mild to severe lymphoid depletion which was also reflected in significantly (P less than 0.05) reduced spleen and thymus organ weight to body weight ratios. Since 100 mg/kg of CI-959 produced toxicological and pathological alterations in the exposed rats, these data suggest that CI-959 is not highly or specifically immunotoxic at dosages lower than those that alter conventional toxicological parameters used in new drug testing programs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Novel indolecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic potential of a series of novel indolecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated basophilic leukocytes obtained from allergic donors. Optimal inhibition is exhibited by compounds with 3-alkoxy, 5-methoxy, and 1-phenyl substituents on the indole core structure. Compound 8d (5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide; designated CI-949) is a potent inhibitor of histamine release from human basophils and from guinea pig and human chopped lung.

Animals↗

PubMed1987

Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: mechanism of inhibitory activity.

3,7-Dimethoxy-4-phenyl-N-1H tetrazol-5-yl-4H-furo[3,2-b]-indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitory of human neutrophil functions in response to a variety of stimuli. In this report, the effects of CI-922 on specific processes involved in stimulus-response coupling are evaluated. CI-922 does not inhibit human neutrophil phospholipase C or protein kinase C activities. CI-922 is shown to inhibit calmodulin-dependent enzyme activation. The calmodulin antagonist activity is confirmed by calmodulin-Sepharose affinity chromatography. These results suggest that CI-922 inhibits neutrophil activation by preventing the activation of calmodulin-dependent enzymes, implying a critical role for such enzymes in stimulus-response coupling.

Azoles↗

PubMed1987

Specific inhibition of phorbol ester and DiC8-induced histamine release from human basophils by the protein kinase C inhibitors, H-7 and H-9.

The release of histamine and other inflammatory mediators from human basophils is triggered by numerous stimuli, including chemical, physical and receptor-mediated activators. Several mechanisms of cell activation including protein kinase C activation have been proposed to operate in these cells. We used phorbol ester and DiC8 to induce histamine release from human basophils and the protein kinase C inhibitors H-7 and H-9 to inhibit this release. Both DiC8 and TPA induced histamine release were inhibited by H-7 (ID 50 = 37 mcM) and H-9 (IC 50 = 20 mcM). However, anti-IgE, fmlp and A23187-induced histamine release were unaffected. In contrast, the calmodulin antagonists W-7 and perphenazine effectively inhibited histamine release by all five stimuli. Therefore, different biochemical pathways appear to be critical for basophil activation depending on the nature of the stimulus used.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1987

Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: differential inhibition of responses to a variety of stimuli.

The allergic mediator release inhibitor 3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo[3,2-b]indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitor of human neutrophil functions in vitro. Over a concentration range from 1 to 100 mumol CI-922 inhibits the chemotactic response of neutrophils to the synthetic chemotaxin N-formyl-methionyl-leucyl-phenylalanine (FMLP). CI-922 also inhibits respiratory and secretory responses of neutrophils in response to agents that stimulate phospholipase C-dependent phosphoinositide hydrolysis to generate the second messengers inositol 1,4,5, trisphosphate and 1,2 diacylglycerol, including: the plasma membrane receptor-specific ligands FMLP and C5a; serum-opsonized zymosan; concanavalin A; and the guanine nucleotide regulatory protein-specific stimulus guanosine-5'-0-(3-thiotriphosphate) (GTP gamma S). CI-922 also inhibits neutrophil functions stimulated by the calcium ionophore A23187. In contrast, CI-922 does not inhibit neutrophil responses to protein kinase C-specific stimuli such as phorbol 12-myristate 13-acetate (PMA) or L-alpha-1,2 dioctanoylglycerol (DiC8). CI-922 also fails to inhibit the synergistic activation of the respiratory burst by suboptimal concentrations of PMA and calcium ionophore A23187. The observation that CI-922 inhibits neutrophil responses to a variety of soluble and particulate stimuli, excluding protein kinase C-specific stimuli, allows us to postulate the site of action of the compound. We propose that CI-922 inhibits neutrophil activation at a site distal to signal transduction through the guanine nucleotide regulatory protein required for second messenger generation but proximal to phosphorylation reactions mediated by protein kinase C and calmodulin-dependent protein kinases.

Azoles↗

PubMed1986

Repeatable antigen-induced contractions of isolated guinea pig lung strips are mediated by leukotriene.

Lung strips from actively sensitized guinea pigs were repeatedly contracted by antigen (ovalbumin, OA) challenge in the presence of the antihistamine (H1) mepyramine. At lower concentrations of OA, hourly challenges gave reproducible and consistent responses. High-concentration OA resulted in desensitization, with two to six contractions being very weak. The antigen concentration affected not only the force of contraction, but other parameters including the time to peak effect, the protraction of the peak effect, and the repeatability of the force and time to peak. Low concentrations of OA induced a response which peaked by 6-8 min and decreased by about 30% after 15 min, while high-concentration OA resulted in a contraction which peaked later and did not relax. These data suggest that different 'early' and 'late' mediators may be involved depending on the 'activation state' or the mechanisms that predominate in the contraction response as a result of the amount of stimulation by antigen. Leukotriene apparently mediates the peak and the 15-min contraction since both were inhibited completely by FPL-55712 (IC50 = 8 microM) or NDGA (IC50 = 5 microM). These repeated, leukotriene-mediated contractions of isolated lung may mimic the clinical situation (chronic exposure to low amounts of antigen) of allergic disease and may be used to study the modulation of lung responses and desensitization phenomena.

Animals↗

PubMed1985

Differential inhibition of histamine release from human basophils induced by antigen, anti-IgE or N-formyl-L-methionyl-L-leucyl-L-phenylalanine.

We report differential effects of various compounds on inhibition of histamine release from washed leukocytes stimulated through IgE (using antigen or anti-IgE antibody) or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) receptors. Inhibition of IgE-induced release was seen for several compounds listed in order of potency (IC50 in microM): CI-922 (3,7-dimethoxy-4-phenyl-N-(1-H-tetrazol-5-yl)-4-H-furo-[3, 2-b]-indole-2-carboxamide, 1-arginate) less than NDGA less than BW755c less than proxicromil less than isamoxole less than phenidone. Other compounds including FPL 55712, meclofenamate, and indomethacin were inactive or enhanced IgE-mediated release. When FMLP was used to stimulate histamine release the order of potency (IC50) changed: meclofenamate = FPL 55712 = proxicromil less than CI-922 less than NDGA = BW755c less than indomethacin less than isamoxole = phenidone. The inhibition of FMLP-induced histamine release by FPL 55712, meclofenamate and indomethacin in the absence of inhibition (or even enhancement) of histamine release by the IgE mechanism suggests that different pathways of activation and/or control are critical in the release process when different stimuli are used to activate basophils.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗