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Biomedical subjects

C D Wright

Publications and source records attributed to C D Wright.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1990

New trends in the surgical treatment of non-small cell lung cancer.

Lung cancer is the most common cause of cancer death in both men and women now. Limited resections have proven to be safe and effective in high-risk patients. Sleeve resection now offers both conservation of pulmonary function and enhanced resectability to select patients. Chest wall resections in association with pulmonary resection offer worthwhile survival if the mediastinal lymph nodes are not involved. Solitary cerebral metastases can now be resected with favorable results in carefully selected patients. New treatment strategies, such as neoadjuvant therapy, are on the horizon for advanced stage patients. Operative mortality has declined significantly compared to past decades. While the prognosis for most patients with non-small cell lung cancer remains grim, surgery is now possible in select subgroups with relatively good results.

Carcinoma, Non-Small-Cell Lung↗
PubMed1989

Formation of chloramine derivatives of histamine: role of histamine chloramines in bronchoconstriction.

Hypochlorous acid generated by myeloperoxidase reacts with histamine to produce chloramines. At pH 7, one mole of histamine monochloramine (HisCl) was generated per mole of H2O2 provided as substrate for myeloperoxidase. At pH 5, one mole of histamine dichloramine (HisCl2) was generated per two moles of H2O2. HisCl and HisCl2 had two and four oxidizing equivalents per molecule, respectively. In vitro, 30 microM HisCl and HisCl2 induced mepyramine-sensitive guinea pig lung parenchyma contraction with 89 and 56 percent of the response of an equivalent concentration of histamine. Pretreatment of lung strips with chloramines reduced the subsequent contractile response of the tissues to methacholine. These results suggest that H-1 histamine receptors provide for targeting of histamine chloramines to pulmonary tissue which may facilitate modification of tissue responses.

Animals↗
PubMed1989

Generation of nitric oxide by human neutrophils.

Human neutrophils were evaluated for their ability to generate nitric oxide. Neutrophils incubated with superoxide dismutase at 37 degrees C produce nitrite anion at a rate of 1.8 nmols/2 x 10(6) cells/30 min, providing indirect evidence of nitric oxide production. Incubation of the neutrophils with concentrations of serum-opsonized zymosan, N-formyl-methionyl-leucyl-phenylalanine, or phorbol myristate acetate sufficient to stimulate the respiratory burst and lysosomal enzyme release caused no additional nitrite anion production. Glass wool-adherent neutrophils exhibited a similar dissociation of nitrite anion production from the respiratory burst and lysosomal enzyme release. Direct evidence for nitric oxide production was also obtained using nitric oxide-specific chemiluminescence. These results demonstrate that human neutrophils are capable of generating nitric oxide.

Anions↗
PubMed1988

Candidacidal activity of myeloperoxidase: characterization of myeloperoxidase-yeast complex formation.

We have previously demonstrated the ability of human neutrophil myeloperoxidase to bind to cell wall mannan polysaccharide isolated from Candida albicans. This binding capacity provides for association of the enzyme with target yeast which is essential for efficient candidacidal activity. In this report, we further consider the role of the mannan-binding property of myeloperoxidase in the candidacidal activity of the enzyme. Solubilized mannan antagonizes binding of the enzyme to yeast, suggesting that mannan may be a primary component of the fungal cell wall which serves as a target for binding of myeloperoxidase. Myeloperoxidase is shown to form complexes with both solubilized mannan and Candida yeast, with Kds of 0.97 x 10(-5) M and 1.2 x 10(-5) M, respectively. The interaction between myeloperoxidase and mannan does not allow the enzyme to readily dissociate from the surface of target yeast. As a result, the enzyme may be unable to dissociate from dead yeast to become available for binding to additional fungal targets.

Candida albicans↗
PubMed1988

Rectal necrosis after pelvic crush injury.

A case is described in which transmural necrosis of the rectum occurred following a severe pelvic crush injury in an obese man. The necrosis presumably resulted from occlusion of both internal iliac arteries, disruption of the pelvic collateral circulation, and as a result of direct rectal contusion.

Adult↗
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

Comparison of the roles of calmodulin and protein kinase C in activation of the human neutrophil respiratory burst.

The roles of calmodulin and protein kinase C in the activation of the human neutrophil respiratory burst were characterized pharmacologically. The protein kinase C inhibitors 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) and N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9) did not inhibit superoxide anion generation by neutrophils stimulated for 30 minutes with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) or 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA). However, H-7 did depress superoxide production during the first 5 minutes following stimulation. In contrast, the specific calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and the dual calmodulin antagonist/protein kinase C inhibitor trifluoperazine (TFP) were potent inhibitors of the response throughout the 30 minute incubation. Stimulation of neutrophils with submaximal doses of FMLP or PMA failed to promote inhibition of the respiratory burst by H-7 or H-9, but did stimulate a respiratory burst response which was not inhibited by TFP or W-7. These results suggest that while protein kinase C may play a role in the initiation of the respiratory burst response, propagation of the response is dependent on calmodulin-dependent processes. The inability of TFP and W-7 to inhibit superoxide anion generation in response to submaximal stimulatory doses of FMLP or PMA suggests that calmodulin-independent processes may also be involved in activation of the respiratory burst.

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↗
PubMed1987

Superior sulcus lung tumors. Results of combined treatment (irradiation and radical resection).

Twenty-one patients underwent combined therapy (irradiation and radical resection) for a Pancoast tumor at the Massachusetts General Hospital between 1976 and 1985. All patients underwent en bloc removal of the apical chest wall and underlying lung. In addition four patients required subclavian artery resection, and in five patients a portion of the vertebral body was resected. There were three operative deaths. Median survival was 24 months and actuarial survival rate was 55% at 3 years and 27% at 5 years. Long-term palliation of pain was achieved in 72% of the patients. Involvement of the subclavian artery, vertebral body, or rib did not preclude long-term survival. Computed tomographic scanning in these patients is often indeterminate regarding invasion of chest wall structures but is more helpful than plain films alone. When compared to recent series in which irradiation alone was used, the combined approach appears to produce better results.

Actuarial Analysis↗
PubMed1986

The protein kinase C inhibitors H-7 and H-9 fail to inhibit human neutrophil activation.

The protein kinase C inhibitors 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) and N-(2-aminoethyl)-5-isoquinolinesulfonamide (H-9) were examined for their ability to inhibit human neutrophil activation. At concentrations up to 100 micromolar, these compounds failed to inhibit either respiratory burst or the secretory response of neutrophils stimulated with particulate (serum-opsonized zymosan) or soluble (A23187, FMLP, PMA) stimuli. In contrast, the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7) inhibited both oxygen radical generation and lysosomal enzyme release in response to the same stimuli. These results suggest that calmodulin-dependent enzymes, rather than protein kinase C, may be essential for neutrophil activation.

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