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D C Anderson

Publications and source records attributed to D C Anderson.

At least 91 records · Page 5Linked to original sources
PubMed1996

Pharmacokinetics and metabolism of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470, AGM-1470) in rhesus monkeys.

The metabolic disposition and pharmacokinetics of TNP-470 were investigated in rhesus monkeys following intravenous administration of 5 mg/kg of [3H]-TNP-470. Rapid and extensive metabolism of parent drug to six metabolites occurred as demonstrated by the absence of unchanged drug in plasma and urine at time points as early as 6 min after administration. Substantial, yet variable, plasma levels of M-IV were detected in all three monkeys with a mean Cmax value of 3.54 microM. Five other metabolites, labeled M-I, M-II, M-III, M-V and M-VI, were also detected in biological fluids of monkeys. M-II, M-V and M-VI exhibited similar kinetic profiles with apparent plasma elimination half-life values of 0.91 +/- 0.37, 2.42 +/- 0.13 and 1.19 +/- 0.29 h respectively. In contrast, M-I, M-III and M-IV exhibited much shorter apparent plasma half-life values of 30 min or less. Urinary recovery within 36 h represented only 19.90 +/- 6.09% of the total administered dose. No radioactivity was detected beyond 36 h and during a 15-day sample collection period, suggesting that nonrenal (biliary) elimination of TNP-470 metabolites is a predominant excretion route in nonhuman primates. This study provides the first detailed in vivo analysis of TNP-470 metabolism and disposition using an animal model highly predictive of humans, consistent with the detection of the same TNP-470 metabolites in human tissues. A detailed understanding of TNP-470 metabolism and disposition is critical to fully elucidate the pharmacodynamic properties of this new anticancer drug as clinical investigations proceed.

Animals↗
PubMed1996

Extract of Helicobacter pylori induces neutrophils to injure endothelial cells and contains antielastase activity.

BACKGROUND & AIMS: Previous studies indicate that a water extract of Helicobacter pylori promotes leukocyte adhesion and emigration as well as endothelial barrier disruption (increased vascular protein leakage) in rat mesenteric venules. The aims of this study were to assess whether H. pylori extract-activated neutrophils disrupt endothelial cell monolayers and to identify the mechanisms involved in this process. METHODS: Human neutrophils were incubated with monolayers of human umbilical vein endothelial cells (HUVECs) in the presence or absence of H. pylori extract. RESULTS: H. pylori extract-activated human neutrophils produced endothelial cell detachment from HUVEC monolayers, the severity of which was dependent on the duration of exposure. Endothelial cell detachment was prevented by a monoclonal antibody directed against CD11/CD18 on neutrophils or a monoclonal antibody against intercellular adhesion molecule 1 on endothelial cells. HUVEC monolayer disruption was also prevented by superoxide dismutase, catalase, and a monoclonal antibody against elastase. Further studies indicated that H. pylori extract was capable of inhibiting human neutrophil elastase. The antielastase activity was not diminished by oxidants. CONCLUSIONS: These studies indicate that H. pylori extract-activated human neutrophils can disrupt HUVEC monolayers only when human neutrophils are allowed to adhere to HUVECs and may provide an explanation for the H. pylori extract-induced, neutrophil-dependent vascular protein leakage observed in vivo. The possibility that H. pylori releases antiproteases may explain, in part, why this bacterium is so virulent.

Antibodies, Monoclonal↗
PubMed1996

Portal hypertension enhances endotoxin-induced intercellular adhesion molecule 1 up-regulation in the rat.

BACKGROUND & AIMS: Liver disease or portosystemic shunting enhances th e sensitivity to endotoxin. The aim of this study was to investigate whether intercellular adhesion molecule 1 (ICAM-1) expression in response to endotoxin may be dysregulated in an animal model of portal hypertension. METHODS: Portal hypertension was induced by partial portal vein ligation. Sham-operated animals served as controls. ICAM-1 expression was measured using radiolabeled antibodies under baseline conditions or 5 hours after treatment with either endotoxin or recombinant tumor necrosis factor (TNF). Immunoreactive plasma TNF was also measured. RESULTS: Under baseline conditions, ICAM-1 expression in all organs studied was similar in portal-hypertensive and sham-operated rats. ICAM-1 up-regulation after a high dose of endotoxin (5 mg/kg) was similar in both groups of animals. However, portal-hypertensive animals showed a significantly higher ICAM-1 expression in response to low doses of endotoxin (0.1-10 microgram/kg). The response to a low (but not a high) dose of recombinant TNF was also significantly enhanced in portal-hypertensive animals. In addition, portal-hypertensive rats had higher plasma TNF levels after treatment with endotoxin or recombinant TNF. CONCLUSIONS: Portal hypertension induces an exaggerated ICAM-1 up-regulation in response to endotoxin, which is related to an increased production and decreased clearance of the cytokine.

Analysis of Variance↗
PubMed1996

Leukocyte adhesion and hepatic microvascular responses to intestinal ischemia/reperfusion in rats.

BACKGROUND & AIMS: Although it has been reported that gut ischemia/reperfusion (I/R) elicits neutrophil-dependent liver dysfunction, little is known about the kinetics of leukocyte accumulation in the hepatic microcirculation after gut I/R. The aim of this study was to determine the temporal relationship between leukocyte sequestration and oxidative stress in rat liver after occlusion (30 minutes) and reperfusion (60 minutes) of the superior mesenteric artery and assess the effects of neutrophil depletion or immunoneutralization of either intercellular adhesion molecule 1 (ICAM-1) or the leukocyte adhesion glycoprotein CD11/CD18 on the hepatic microvascular responses to gut I/R. METHODS: Leukocyte accumulation, number of nonperfused sinusoids, and autofluorescence of reduced nicotinamide adenine dinucleotide (NADH) were monitored using intravital videomicroscopy both before and after gut I/R. RESULTS: The number of adherent leukocytes in both midzonal and pericentral regions after gut I/R was elevated. Autofluorescence of NADH increased after reperfusion (indicating hypoxia), particularly in the pericentral region. Neutrophil depletion or antibodies to either ICAM-1 or CD11/CD18 blunted the gut I/R-induced increases in NADH autofluorescence in the pericentral region, leukocyte adherence, and nonperfused sinusoids. CONCLUSIONS: Leukocytes accumulate in the liver after gut I/R via interaction of CD11/CD18 and ICAM-1. The leukocytes appear to mediate an oxidative stress, occurring in proximity to nonperfused sinusoids, that may contribute to liver injury.

Animals↗
PubMed1996

Microvascular dysfunction induced by nonsteroidal anti-inflammatory drugs: role of leukocytes.

The objectives of this study were to determine whether 1) the leukocyte-endothelial cell adhesion observed in venules exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) is accompanied by enhanced albumin extravasation, and 2) leukocytes mediate this endothelial cell barrier dysfunction. Intravital video microscopy was used to monitor leukocyte-endothelial cell adhesion and the leakage of fluorescein isothiocyanate-labeled albumin in rat mesenteric venules exposed to either indomethacin or aspirin. Both NSAIDs induced the recruitment of adherent and emigrated leukocytes with temporally related increases in albumin leakage. Agents that effectively decreased or prevented the NSAID-induced leukocyte adherence/emigration (leukotriene B4 receptor antagonist or adhesion molecule-specific monoclonal antibodies) also blocked the corresponding albumin leakage response. These findings indicate that adherent and/or emigrating leukocytes mediate the early endothelial cell barrier dysfunction elicited by NSAIDs.

Animals↗
PubMed1996

Combined inhibition of P-selectin and ICAM-1 reduces myocardial injury following ischemia and reperfusion.

Neutrophil-endothelial cell interactions are mediated by a number of cell adhesion proteins. We investigated the effects of inhibition of P-selectin and intercellular adhesion molecule-1 (ICAM-1), individually or in combination, in the ischemic-reperfused canine myocardium. Monoclonal antibodies PB1.3 (anti-P-selectin) and CL 18/6 (anti-ICAM-1) were administered to dogs subjected to coronary artery occlusion and reperfusion. After reperfusion, untreated dogs experienced a 61% decline (P < 0.01 vs. baseline) in myocardial blood flow and a ninefold increase in ischemic zone neutrophil accumulation (4.7 +/- 0.9 U/100 mg tissue myeloperoxidase activity). In contrast, PB1.3 and CL 18/6 administered individually preserved myocardial blood flow (11 and 24% decrease from baseline, respectively, both P < 0.01 vs. saline), and significantly attenuated myeloperoxidase activity (1.4 +/- 0.3 and 1.5 +/- 0.26 U/100 mg tissue, respectively, both P < 0.01 vs. saline). PB1.3 and CL 18/6 in combination resulted in significant coronary vascular and myocardial protection that was not superior to treatment with either antibody alone. Thus the coadministration of anti-P-selectin and anti-ICAM-1 monoclonal antibodies does not enhance the degree of myocardial protection in this model of reperfusion injury.

Animals↗
PubMed1996

Role of intercellular adhesion molecule-1 in antigen-induced lung inflammation in brown Norway rats.

We investigated the involvement of intercellular adhesion molecule-1 (ICAM-1; CD54) in ovalbumin (OA) antigen-induced lung inflammation in sensitized Brown Norway (BN) rats by using flow cytometry and in vivo treatment with a murine monoclonal antibody (MAb), 1A29, directed against rat ICAM-1. OA-challenge induced an eosinophil and lymphocyte-rich accumulation of leukocytes into the airway lumen. Between 75 and 90% of the T cells in bronchoalveolar lavage (BAL) fluid after challenge expressed CD54 and CD11a and were of the memory phenotype. 1A29 treatment produced dose-related increases in circulating 1A29 and blood neutrophils. In the BAL fluid of 1A29-treated animals, significant (P < 0.05) reductions in the numbers of eosinophils and lymphocytes, but not neutrophils or alveolar macrophages, were observed in association with a reduced inflammatory pathology in lung tissue. 1A29 administration reduced the number of detectable ICAM-1 binding sites on T cells in peripheral blood and BAL fluid examined ex vivo by flow cytometry. We conclude that ICAM-1 is critically important for the antigen-specific recruitment of eosinophils and lymphocytes into the lungs.

Animals↗
PubMed1996

Heterogeneity of expression of E- and P-selectins in vivo.

A novel technique involving radiolabeled monoclonal antibodies was used to characterize and compare the expression of E- and P-selectin on unstimulated, histamine-challenged, and endotoxin-challenged endothelial cells in various tissues of the mouse. Under unstimulated conditions, E-selectin was absent in all organs, but significant expression of P-selectin was observed in several organs. Histamine induced a rapid time-dependent upregulation of P-selectin, with the largest responses observed in mesentery and lung. Significant fold elevations in P-selectin expression occurred as early as 5 minutes after the histamine injection and remained elevated up to 1 hour. Histamine-induced P-selectin upregulation was inhibited by the H1 receptor antagonist diphenhydramine, whereas the H2 receptor antagonist cimetidine had no effect. Endotoxin (lipopolysaccharide [LPS]) also induced a time-dependent expression of P-selectin that reached a maximum between 4 and 8 hours after endotoxin administration. LPS-induced upregulation of P-selectin was greatest in heart and stomach, which exhibited insignificant constitutive expression of P-selectin. LPS also induced a time-dependent upregulation of E-selectin, with maximal expression occurring 3 to 5 hours after intraperitoneal administration. The lung and small intestine exhibited the largest responses to LPS challenge. Histamine administration did not affect E-selectin expression in any tissue. E- and P-selectin-deficient mice were used to test the specificity of monoclonal antibody binding in unstimulated, histamine-challenged, and LPS-stimulated tissues. Vascular binding of the radiolabeled E-selectin and P-selectin monoclonal antibodies was not observed in the respective deficient mice. These findings suggest that P-selectin is constitutively expressed on vascular endothelium in some tissues of the mouse and that there are significant regional differences in the magnitude and time course of histamine- and endotoxin-induced P-selectin expression. In contrast, E-selectin appears to be absent on unstimulated vascular endothelium but is upregulated within 3 hours after the administration of endotoxin in most tissues.

Animals↗
PubMed1996

Diminished soluble and total cellular L-selectin in cord blood is associated with its impaired shedding from activated neutrophils.

We have previously shown that surface levels of the adhesive glycoprotein, L-selectin, are diminished on cord blood neutrophils (polymorphonuclear leukocytes, PMN) and associated with impaired adherence to endothelium under flow conditions. To test the hypothesis that diminished surface levels reflect a total cellular deficiency, we measured L-selectin in PMN lysates and plasma from cord and adult blood. L-selectin content was decreased in cord blood PMN lysates compared with those of adults by both Western blot analyses and ELISA (cord blood, 1195 +/- 160 pg/mL; adult, 1870 +/- 260 pg/mL; X +/- SEM; p < 0.05). Soluble L-selectin levels were also decreased in cord blood plasma (324 +/- 24 ng/mL versus 537 +/- 28 ng/mLiter in adult plasma, p < 0.01). To evaluate L-selectin function, we next compared the dose dependent effect of several chemoattractants on shedding of L-selectin from cord blood and adult PMN. Adult PMN showed greater overall shedding of L-selectin as compared with cord blood PMN after stimulation with fMet-Leu-Phe (p < 0.03) and granulocyte-macrophage colony-stimulating factor (p < 0.02). In contrast, shedding of L-selectin was similar between groups after IL-8 tested stimulation. We conclude that cord blood PMN have a decreased cellular content of L-selectin in addition to an impaired ability to shed surface L-selectin in response to specific inflammatory mediators.

Adult↗
PubMed1996

Differential effect of aspirin versus warfarin on clinical stroke types in patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators.

The Stroke Prevention in Atrial Fibrillation II study compared the efficacy and safety of aspirin and warfarin in patients with atrial fibrillation. Three neurologists, blinded to patient therapy, categorized the pathophysiology of ischemic strokes that occurred in the trial based on predetermined clinical criteria. Upon analyzing the patients being treated with these two drugs, warfarin proved significantly more effective than aspirin in preventing cardioembolic strokes (p = 0.005) and strokes of uncertain pathophysiology (p = 0.01). There was no significant difference in the efficacy for prevention of noncardioembolic strokes.

Aged↗
PubMed1996

Genetic components for milk production of tarentaise, hereford, and tarentaise x hereford cows.

The objective of this study was to estimate genetic components for milk production of Hereford (HH), Tarentaise (TT), and Hereford x Tarentaise or Tarentaise x Hereford (HT) cows under range conditions at the Northern Agricultural Research Center, Havre, MT. Milk production of 494 cow-calf pairs was estimated by the weigh-suckle-weigh procedure from 1989 to 1994. Milk production and cow and calf weights were measured at 40 d (early) and 120 d (late) of lactation. The mating scheme was a 3 x 3 design in which HH, HT, and TT cows were mated with HH, HT, and TT sires, producing calves that were varying percentages of Hereford and Tarentaise. Data were analyzed by least squares procedures according to a model that included year, age of cow, sex of calf, linear regression on calf age, and linear regressions on coefficients that coded for various genetic components. These genetic components were breed individual, breed maternal, breed grand maternal, individual heterosis (calf heterosis), and maternal heterosis (cow heterosis). Coefficients for genetic components were such that breed effects estimated TT-HH and regressions on heterosis values estimated the full effect of heterosis. The breed individual genetic component was significant only for calf early and late weights; Tarentaise calves were lighter. Breed maternal was significant for most traits, and these effects were positive for milk production (2.16 and 3.77 kg/d for early and late, respectively) and calf weights but negative for cow weights. Individual heterosis was not significant for early milk production but was significant for late milk production (1.05 kg/d) and calf weights (2.3 and 8.1 kg for early and late, respectively). Maternal heterosis was significant for most traits and increased early milk production (1.25 kg/d), calf weights (4.5 and 5.8 kg for early and late, respectively), and cow weights (18.1 and 6.0 kg for early and late, respectively).

Analysis of Variance↗
PubMed1996

Factors influencing genetic evaluations of linebred Hereford cattle in diverse environments.

Data from four closely related Line 1 Hereford herds were used to estimate variance components and predict EPD for birth weight (BWT), weaning weight (WWT), and postweaning gain (PWG). Herds were located in diverse environments and differed in level of phenotypic performance. Within-herd BWT analyses considered effects of inbreeding of calf and dam, sex, age of dam (AOD), and contemporary group as fixed and direct and maternal additive genetic effects and permanent environmental effects due to dam as random. The model for WWT included these effects and age of calf. The model for PWG included inbreeding of calf, contemporary group, and direct additive genetic effects. Across-herd analyses were conducted with additional models. The first considered herd-specific inbreeding, sex, and AOD effects. A second model pooled these effects across herds, and a third included pooled sex and AOD effects but ignored inbreeding. Across-herd EPD, including and ignoring inbreeding, were predicted for WWT preadjusted with standard adjustments for Hereford cattle. Within-herd analyses indicated potential for heterogenous genetic and environmental variances across herds. Across-herd variance component estimates were consistent, regardless of the model. Estimates of genetic trends indicated potential for bias in genetic evaluations resulting from choice of model. Differences in magnitude of fixed effects between herds were observed. Genetic evaluations were different when pooled or herd-specific fixed effects were used. Allowance for individual herd differences in fixed effects in across-herd evaluations is suggested.

Aging↗
PubMed1996

Apigenin inhibits tumor necrosis factor-induced intercellular adhesion molecule-1 upregulation in vivo.

OBJECTIVE: Apigenin is a flavonoid that effectively blocks intercellular adhesion molecule-1 (ICAM-1) upregulation and leukocyte adhesion in response to cytokines in vitro. In the present study, we characterized the effects of tumor necrosis factor (TNF) on ICAM-1 expression in different tissues of the rat. We then assessed whether apigenin alters this response. METHODS: ICAM-1 expression was measured under baseline conditions or 5 h after treatment with rTNF. We used 125I-labeled anti-rat ICAM-1 monoclonal antibody (mAb) and an isotype-matched control mAb labeled with 131I to correct for nonspecific accumulation of the binding mAb. Animals were pretreated with either placebo, apigenin, narigenin (a flavonoid without inhibitory effect in vitro), or vehicle. Additional groups of animals were treated with either allopurinol, glutathione, dimethyl-thiourea, or an anti-CD18 monoclonal antibody in order to assess possible actions of flavonoids that were mediated via free radical scavenging or through interference with neutrophil function. RESULTS: Treatment with rTNF resulted in a marked increase in ICAM-1 expression in all organs studied. The magnitude of the response varied in different organs and increases ranged from onefold (lung) to threefold (muscle). Treatment with apigenin blocked ICAM-1 upregulation in organs with low to intermediate responses to rTNF and it significantly attenuated the increased ICAM-1 expression in organs that normally exhibit more marked upregulation. Treatment with narigenin or vehicle did not affect rTNF-induced ICAM-1 upregulation in all tissues studied. Pretreatment with either allopurinol, free radical scavengers, or anti-CD18 monoclonal antibody did not affect the ICAM-1 upregulatory response to rTNF. CONCLUSIONS: TNF-induced ICAM-1 upregulation in vivo effectively is blocked by apigenin through a mechanism that is unrelated to free radical scavenging or leukocyte function.

Animals↗
PubMed1996

U-73122: a potent inhibitor of human polymorphonuclear neutrophil adhesion on biological surfaces and adhesion-related effector functions.

We have reported that U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole- 2,5-dione) an inhibitor of phospholipase C-dependent processes in human polymorphonuclear neutrophils (PMN) and platelets, potently suppresses the responsiveness of suspended PMN and platelets to receptor agonists. We demonstrate here that U-73122 caused a concentration-dependent (10-800 nM) inhibition of N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor-alpha (TNF alpha), interleukin-8 and phorbol myristate acetate (PMA)-triggered PMN adhesion on fibronectin, fetal bovine serum or keyhole limpet hemocyanincoated microtiter plates. U-73122 also inhibited PMN adherence to and transmigration through TNF-alpha-activated endothelium (IC50 < 50 nM). Further, U-73122 suppressed interleukin-8, N-formylmethionyl-leucyl-phenylalanine and PMA-stimulated up-regulation of the beta 2-integrin, Mac-1 (CD11b/CD18), on the PMN surface (IC50 < 1.3 microM). U-73122 also caused a time-(15-120 min) and concentration-dependent inhibition (IC50 = 25-100 nM) of the N-formyl-methionyl-leucyl-phenylalanine-, TNF alpha- and PMA-elicited adhesion-dependent, oxidative burst, measured as hydrogen peroxide (H2O2) production, in PMN. The CD18-dependent extracellular release of lactoferrin from PMN activated with these stimuli was also suppressed by U-73122. U-73343 (1-[6-[[17 beta-3- methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidine dione), a close analog of U-73122, did not affect PMN responsiveness.

Animals↗
PubMed1996

The relationship between upper gastrointestinal hemorrhage and drug use: a case control study.

The relationship between upper gastrointestinal hemorrhage and drug use was studied in 251 Chinese patients (179 men, 72 women) admitted to the Prince of Wales Hospital, Hong Kong, and control subjects matched for age and sex. There was a highly significant difference between the cases and control subjects in the use of NSAIDs (odds ratio 14.0, p < 0.00001), ulcer healing drugs (odds ratio 12.5, p < 0.00001), and Chinese proprietary medicines (odds ratio 16.0, p < 0.00001). There was also a significant difference in the use of analgesics (odds ratio 14.0, p = 0.001), paracetamol (odds ratio 2.5, p = 0.01), antacids (odds ratio 2.7, p < 0.001) and unknown drugs (odds ratio 4.7, p < 0.001). Cases also differed from control subjects regarding the use of tobacco (odds ratio 2.3, p < 0.001) and alcohol (odds ratio 1.7, p = 0.02), and the presence of peptic ulcer symptoms (odds ratio 29.8, p < 0.00001). Significantly more control subjects than cases were receiving aspirin, cardiovascular drugs, bronchodilators, oral hypoglycemic drugs/lipid-lowering drugs, and anticonvulsants/hypnotics, due to the inevitable differences in disease pattern between the 2 groups. NSAID use was a major factor associated with upper gastrointestinal hemorrhage from primarily peptic ulcers. Differences in the use of other drugs may reflect variations in disease patterns between cases and controls, the common practice of self-medication in Hong Kong, and the concomitant use of NSAIDs and ulcer healing drugs/antacids.

Adolescent↗
PubMed1995

Selective inhibition of E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression by inhibitors of I kappa B-alpha phosphorylation.

The promoters of the E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) genes contain recognition sequences for the inducible nuclear transcription factor kappa B (NF-kappa B). We demonstrate that the appearance of NF-kappa B DNA-binding activity in the nucleus of TNF-alpha-stimulated HUVEC is associated with the rapid phosphorylation and subsequent degradation of I kappa B-alpha, the cytoplasmic inhibitor of NF-kappa B. Serine protease inhibitors prevented the TNF-alpha-induced accumulation of phosphorylated I kappa B-alpha, and prevented I kappa B-alpha degradation and the appearance of NF-kappa B DNA-binding activity. These inhibitors had no direct effect upon the ability of NF-kappa B to bind its cognate recognition sequences, nor upon the DNA-binding activities of other transcription factors. Inhibition of I kappa B-alpha proteolysis resulted in the inhibition of the cytokine- and LPS-induced transcriptional up-regulation and cell-surface expression of E-selectin, VCAM-1, and ICAM-1. In contrast, the TNF-alpha-induced expression of plasminogen activator inhibitor-1 and the constitutive expression of ICAM-2 were unaffected. These inhibitors also had no effect on cellular viability or rates of RNA or protein synthesis. Inhibitors of other proteases and various protein kinases had no effect on the cytokine-induced expression of these endothelial adhesion molecules. These findings indicate that it is possible, using a single pharmacologic agent, to selectively inhibit the expression of the E-selectin, VCAM-1, and ICAM-1 genes without affecting the constitutive or inducible expression of other genes. Pharmacologic inhibition of I kappa B-alpha proteolysis represents a novel approach to the development of anti-inflammatory therapeutics.

Cells, Cultured↗