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Biomedical subjects

C D Wright

Publications and source records attributed to C D Wright.

At least 19 recordsLinked to original sources
PubMed1995

Inhibition of E-selectin-, ICAM-1-, and VCAM-1-mediated cell adhesion by benzo[b]thiophene-, benzofuran-, indole-, and naphthalene-2-carboxamides: identification of PD 144795 as an antiinflammatory agent.

It was previously reported that 3-alkoxybenzo[b]thiophene-2-carboxamides exemplified by 1, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide, decreased the adherence of neutrophils to activated endothelial cells by inhibiting the upregulation of the adhesion molecules E-selectin and ICAM-1 on the surface of the endothelium. This finding is extended here to a series of 3-thiobenzo[b]thiophene-2-carboxamides and also heterocyclic analogs of 1, including benzofurans, indoles, and napthalenes. The compounds that inhibited the expression of E-selectin and ICAM-1 had the same effect on the expression of VCAM-1. PD 144795, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide 1-oxide (44), the sulfoxide analog of 1, was orally active in several models of inflammation. The in vitro and in vivo activity of PD 144795 resided predominately in the S-enantiomer.

Administration, Oral↗
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↗
PubMed1992

Characteristics of trabecular bone resorption cavities in patients with chronic renal failure.

Using a computerised technique, resorption cavity characteristics in iliac crest trabecular bone were assessed in 30 patients with chronic renal failure and compared with data obtained from healthy subjects. The mean and maximum cavity depth were significantly greater in the patient group (P less than 0.0001); in addition, cavity area, the percentage of bone being remodelled, the number of cavities per mm trabecular surface and the percentage eroded surface were all significantly greater than in controls (P less than 0.0001). However, the surface length of individual cavities in the patient group did not differ significantly from that of controls. In the patient group, serum intact parathyroid hormone concentrations showed a significant positive correlation with mean resorption cavity depth (r = 0.451, P less than 0.05). Our results demonstrate that the increase in bone resorption associated with hyperparathyroidism secondary to chronic renal failure is due to an increase both in the number and depth of cavities, although the surface extent of individual cavities is normal. These findings indicate that factors determining the length of trabecular surface eroded and the depth of individual resorption cavities are controlled by different mechanisms.

Adult↗
PubMed1992

Combined inter-observer and inter-method variation in bone histomorphometry.

Manual methods for the measurement of bone biopsies have largely been superseded by semi-automatic computerised techniques. Histomorphometrists often use control data obtained by other observers using different methods, thus combining inter-observer and inter-method variation. We have examined the combined effect of inter-method and inter-observer variation on measurements of bone area, osteoid perimeter, and osteoid width in iliac crest biopsies from healthy subjects, one observer using the manual grid system and the other using a semi-automated technique. Inter-observer and inter-method variation were independently determined, and the proportion of each expressed as a percentage of combined error. Our results indicate that the combination of inter-method and inter-observer variation causes significant differences in the values obtained for osteoid perimeter, whereas inter-method variation is mainly responsible for differences in osteoid width values; differences in bone area are largely due to inherent sampling variation. These variations indicate that caution is required when comparison is made with control data from other sources, especially if different techniques are employed.

Analysis of Variance↗
PubMed1992

Reduction of canine myocardial infarct size by CI-959, an inhibitor of inflammatory cell activation.

CI-959, a cell-activation inhibitor that prevents the formation of oxygen-derived free radicals by inflammatory cells, was studied to determine its effects on myocardial infarct size and subsequent scar formation in dogs. The left circumflex coronary artery was occluded for 90 min, followed by 6 h of reperfusion. Drug infusion was started 15 min before reperfusion at a loading dose of 8 mg/kg i.v., followed immediately by 2 mg/kg i.v. infused over 80 min. The infarct size, assessed by TTC staining techniques, was significantly reduced in 12 dogs treated with CI-959 (23.3 +/- 3.6% of the area at risk) when compared to 11 vehicle-treated animals (35.5 +/- 4% of the area at risk, p less than 0.05). This reduction in infarct size was not attributed to changes in regional myocardial blood flow, as measured by radioactive microspheres, or to a reduction in myocardial oxygen demand, as estimated by changes in the rate-pressure product. The scar thickness, measured after a 6-week recovery period in 9 animals treated with CI-959, was not significantly reduced in comparison with 11 controls. In vitro, CI-959 effectively inhibited oxygen free radical formation by canine neutrophils. The results of this study show that CI-959 significantly reduces the myocardial infarct size without causing scar thinning, which might lead to ventricular aneurysm, and suggests the most likely mechanism for its beneficial action is the prevention of formation of toxic oxygen radicals.

Animals↗
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

The effects of (R)-N-(1-methyl-2-phenylethyl) adenosine (L-PIA), a standard A1-selective adenosine agonist on rat acute models of inflammation and neutrophil function.

L-PIA, a standard A1-selective adenosine agonist, was evaluated orally in carrageenan (CRG)- and reverse passive arthus-pleurisy. White blood cell (WBC) and exudate accumulation were assessed four hours after induction of the inflammatory response. L-PIA inhibited WBC accumulation in both models with ID50's of 4.37 and 4.42 mg/kg, respectively. In contrast, exudate was inhibited by L-PIA only in the CRG pleurisy model (ID50 = 1.01 mg/kg). In mechanistic studies, L-PIA reversed the drop in circulating neutrophil count which occurred within 15 minutes after CRG injection, suggesting that L-PIA may inhibit adhesion of the cells to the endothelium. The effects of L-PIA on several parameters of rat neutrophil function were determined. Enzyme release, O2-, TXB2, and LTB4 production were monitored in response to FMLP and opsonized zymosan (SOZ) stimulation. At high concentrations, L-PIA had a mild inhibitory effect on O2- release in response to FMLP and had a moderate effect on arachidonic acid metabolite production in response to both stimuli. The other response were unaffected. These results suggest that L-PIA may prevent diapedisis or neutrophil adhesion to the endothelium, but has a minimal effect on enzyme release, O2-, LTB4 and TXB2 production.

Adenosine↗
PubMed1990

The antiinflammatory effects of adenosine receptor agonists on the carrageenan-induced pleural inflammatory response in rats.

Adenosine and adenosine receptor agonists have a variety of inhibitory effects on the generation of inflammatory mediators by neutrophils and other cell types. In human neutrophils stimulated with the chemotactic peptide FMLP, adenosine agonists inhibit O2- generation and degranulation. Because these findings suggest that the agonists may have potential as antiinflammatory agents, several compounds were evaluated for effects on the exudative and cellular phases of carrageenan-induced pleural inflammation in rats. All of the agonists tested inhibited both parameters of the inflammatory response. Inhibition appeared to correlate better with binding to the A1 than to the A2 receptor and was reversible by a known adenosine receptor antagonist, 8-phenyltheophylline. In mechanistic studies, R-N-(1-methyl-2-phenylethyl)adenosine, a standard A1 selective agonist, reversed the drop in circulating neutrophil count that occurs after injection of carrageenan. These results suggest that the agonists may prevent cell emigration by inhibiting adhesion to the endothelium or diapedesis. In addition (R)-N-(1-methyl-2-phenylethyl)adenosine had weak inhibitory effects on superoxide production by FMLP-stimulated rat neutrophils. Control studies showed that the effects of the agonists were not the result of agonist-induced hypotension nor corticosterone production by the adrenal glands. These findings indicate that adenosine receptor agonists are effective new pharmacologic tools for the study of inflammatory processes.

Adenosine↗
PubMed1990

Differential inhibition of human neutrophil functions. Role of cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase.

Multiple molecular forms of cyclic nucleotide phosphodiesterase have been characterized in various tissues and cells according to their substrate specificity, intracellular location, and calmodulin dependence. The purpose of this study was to evaluate the possible involvement of different molecular forms of phosphodiesterase in regulating the respiratory burst and lysosomal enzyme release responses of human neutrophils. Treatment with the selective cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase inhibitors Ro 20-1724 or rolipram, or the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), resulted in inhibition of respiratory burst stimulated by the chemoattractants formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) (IC50 values: 0.71-17 microM) and complement fragment C5a (IC50 values: 61-93 microM), but did not inhibit phagocytosis-stimulated respiratory burst (less than 10% inhibition at 100 microM). Selective inhibitors of calmodulin-dependent phosphodiesterase (ICI 74,917), calmodulin-insensitive, cyclic GMP-specific phosphodiesterase (M & B 22,948), cyclic GMP-stimulated phosphodiesterase (AR-L 57), or cyclic AMP-specific, cyclic GMP-inhibited phosphodiesterase (amrinone and cilostamide) exhibited little or no inhibitory effect on FMLP- or phagocytosis-stimulated respiratory burst (0-42% inhibition at 100 microM). Regulation of neutrophil activation by phosphodiesterase was also response specific, as Ro 20-1724, rolipram and IBMX were less potent inhibitors of FMLP-induced lysosomal enzyme release (0-14% inhibition at 100 microM). Analysis of human neutrophil preparations confirmed the existence of a cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase, which was associated with the particulate fraction of the cell. These results demonstrate a role for the cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase in the regulation of human neutrophil functions, which appears to be both stimulus specific and response specific.

1-Methyl-3-isobutylxanthine↗
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

The relationship between spinal trabecular bone mineral content and iliac crest trabecular bone volume.

The relationship between spinal trabecular bone mineral density and iliac crest trabecular bone volume has been studied in 84 patients, 23 with primary osteoporosis, 19 with osteoporosis secondary to inflammatory bowel disease, and 42 with nonsteroid-treated rheumatoid arthritis. Spinal trabecular bone mineral density was measured in the first three lumbar vertebrae by quantitative computed tomography, and iliac crest trabecular bone volume was assessed histomorphometrically in sections from trans-iliac biopsies using computerized techniques. In all 84 patients, there was a significant positive correlation between the two measurements (r = 0.60, P less than 0.001). However, when the three patient groups were analyzed separately, a significant correlation was found in the group with secondary osteoporosis (r = 0.65, P less than 0.01) but not in the patients with primary osteoporosis (r = 0.07) or rheumatoid arthritis (r = 0.19). These results indicate that the relationship between spinal trabecular bone mineral density and iliac crest trabecular bone volume differs according to the underlying disease process, these differences possibly reflecting variations in skeletal patterns of bone loss in different types of osteoporosis.

Adolescent↗
PubMed1990

Effect of omental, intercostal, and internal mammary artery pedicle wraps on bronchial healing.

Bronchial transection and devascularization is necessary in the course of sleeve resection or lung transplantation, leaving distal bronchial segments ischemic and subject to stricture or dehiscence. Thirty mongrel dogs underwent left lung autotransplantation. The bronchial anastomosis was wrapped with omentum (n = 9), intercostal muscle pedicle (n = 9), or internal mammary artery pedicle grafts (n = 6). Six control animals underwent bronchial anastomosis without an external wrap. Bronchial revascularization by capillary ingrowth from the pedicle to the bronchial submucosal plexus was demonstrated with all three types of vascular pedicle grafts; however, more consistent and confluent vascular ingrowth was provided by internal mammary artery pedicle grafts. Additionally, the bronchial anastomotic cross-sectional area was significantly better in the internal mammary artery group (84.5 +/- 3.3) as compared with that of the omental (68.4 +/- 8.3), intercostal muscle (66.9 +/- 10.9), or control groups (70.2 +/- 7.6). An internal mammary artery pedicle graft and the presence of dense confluent submucosal vascular ingrowth from any pedicle graft were independently predictive (p less than 0.05) of minimizing bronchial anastomotic narrowing. These data are consistent with previous findings suggesting that omental and intercostal muscle pedicle grafts promote early bronchial revascularization; moreover, the data demonstrate the superiority of an internal mammary artery pedicle graft to provide submucosal vascular ingrowth and to minimize anastomotic stenosis.

Anastomosis, Surgical↗
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

Primary mediastinal nonseminomatous germ cell tumors. Results of a multimodality approach.

Before cisplatin-based chemotherapy, long-term survival after resection of primary mediastinal nonseminomatous germ cell tumors was unusual. We reviewed the case histories of 48 patients who underwent multimodality treatment for mediastinal nonseminomatous germ cell tumor between 1976 and 1988. Twenty-eight patients received initial therapy at Indiana University and 20 were referred after having had unsuccessful initial therapy elsewhere. In 44 patients (92%) the levels of either one or both serum tumor markers were elevated at the time of diagnosis. Five patients had choriocarcinoma, three embryonal carcinoma, 12 yolk sac carcinoma, four teratocarcinoma, 22 mixed cell type, and two had an unclassified type. Twenty-two of the 28 patients in our initial therapy group had a complete response to treatment, as defined by normal serum tumor markers and absence of residual tumor. In this group, 16 patients had resection of residual disease after chemotherapy, four had total or near total resection before chemotherapy, and only two had chemotherapy alone. Seventeen patients are surviving after this treatment with a median survival of 64 months and a 57% 5-year Kaplan-Meier survival rate. Only two of the 20 patients who were referred for salvage chemotherapy had a complete response. Both required resection of residual disease after salvage chemotherapy. Only one patient survived after this treatment. There was no significant treatment morbidity or mortality. A multimodality approach to primary mediastinal nonseminomatous germ cell tumor with intensive cisplatin-based chemotherapy, emphasis on normalizing serum tumor markers, and aggressive resection of residual disease now offers survival to a significant number of patients.

Adolescent↗