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M M Bednar

Publications and source records attributed to M M Bednar.

43 records · Page 3Linked to original sources
PubMed1987

A neutrophil-derived cytochrome P450-dependent metabolite of arachidonic acid modulates neutrophil behavior.

Recently, the metabolism of arachidonic acid to two unidentified products (Peak 1 and Peak 2) by a cytochrome P-450 dependent mixed function oxidase has been described in canine polymorphonuclear leukocytes (PMNs). This study assessed the biologic activity of one of these metabolites, Peak 2, on PMN function. Peak 2 was formed biologically following addition of exogenous arachidonic acid to canine PMNs pretreated with BW755c to inhibit lipoxygenase and cyclooxygenase enzymes, and purified by high performance liquid chromatography following separation by column chromatography. Peak 2 (20-200 ng/ml) inhibited calcium ionophore A23187-induced aggregation and the second phase of LTB4-induced aggregation. Additionally, Peak 2 inhibited A23187-induced PMN adhesion to columns of Sephadex G-25. BW755c (94 microM), which increased the formation of Peaks 1 and 2 by almost 300%, also inhibited A23187-induced PMN adhesion. In contrast, Peak 2 did not inhibit the release of superoxide anions or immunoreactive LTB4, after stimulation of the PMNs with A23187. Thus, Peak 2 may modulate some activities of canine PMNs. Because the biologic activity of Peak 2 is opposite to that of LTB4, which promotes PMN aggregation and adhesion, and because LTB4 may be metabolized by a cytochrome P-450-dependent mixed function oxidase to less active metabolites, this enzyme system may play a central role in the control of PMN function.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Conversion of arachidonic acid to two novel products by a cytochrome P450-dependent mixed-function oxidase in polymorphonuclear leukocytes.

Canine polymorphonuclear leukocytes metabolize [14C] arachidonic acid into 2 unidentified products, separated by thin-layer chromatography and high performance liquid chromatography, and called peak 1 and peak 2. The formation of peak 1 is maximal at 5 minutes and then declines, while the synthesis of peak 2 increases throughout the 30 minute incubation period. The formation of peak 1 and, to a lesser extent, peak 2, was enhanced after dual inhibition of lipoxygenase and cyclo-oxygenase enzymes with BW755C (94 microns) or nafazatrom (37 microns), or after incubation in a calcium-free buffer. In contrast, the formation of these products was inhibited by SKF-525A (50 microns), suggesting a cytochrome P450-dependent mechanism. The presence of cytochrome P450 in neutrophil microsomes was confirmed by measuring aryl hydrocarbon hydroxylase activity and cytochrome P450 content.

Animals↗
PubMed1984

Renal metabolism of sulindac: functional implications.

We examined the metabolism of the prodrug sulindac sulfoxide and the active moiety, sulindac sulfide, in the isolated perfused kidney of the rabbit. Whether the sulfoxide or the sulfide was infused did not affect notably the pattern of drug efflux. In either case, the inactive sulfoxide and sulfone were the only forms recovered from urinary or venous effluents except for the appearance of a small amount of sulfide in the venous effluent after infusion of the sulfide. In contrast, large amounts of the sulfide were recovered from renal tissue, in addition to the inactive forms, after either prodrug or sulfide administration. We also examined the effects of the prodrug and the sulfide on stimulated release of prostaglandins in response to angiotensin II in the rabbit kidney and to norepinephrine in the rat kidney. Infusion of either 1 microgram/ml of sulindac sulfide or 10 micrograms/ml of sulfoxide inhibited prostaglandin release from both rabbit and rat kidneys. Inclusion of 2% bovine serum albumin in the perfusing medium largely confined radiolabeled forms of sulindac to the vascular space and inhibited oxidative inactivation of sulindac sulfide. However, inhibition of prostaglandin release by sulindac sulfide was only slightly reduced by protein binding. We conclude that 1) the kidney rapidly interconverts sulfide and sulfoxide forms; 2) the forms of sulindac present in renal tissue contrast with the inactive forms recovered from urinary and venous effluents; 3) either prodrug or sulfide administration can result in renal cyclooxygenase inhibition; and 4) protein binding restricts sulindac sulfide primarily to the vascular compartment but does not prevent inhibition of prostaglandin synthesis.

Animals↗
PubMedDate not supplied

Ticlopidine augments luminol-dependent chemiluminescence in human neutrophils.

Neutrophils contribute to the pathophysiology of various ischaemic states. Since many agents thought to be antiplatelet have also been shown to affect neutrophil function, it was of interest to examine the effect of ticlopidine (250 mg, p.o., b.i.d. for three doses), an antiplatelet agent, on fMLP (formyl-methionyl-leucyl-phenylalanine) stimulated neutrophil aggregation and luminol-dependent chemiluminescence in whole blood. Neutrophil aggregation did not significantly change from baseline values during ticlopidine administration. However, luminol-dependent chemiluminescence, an index of respiratory burst metabolism, was noted to be markedly increased during ticlopidine administration. Two hours following the final dose of ticlopidine, the chemiluminescent response (mean +/- SEM, n = 5) was significantly increased from 6.27 +/- 1.88 to 12.66 +/- 2.19 units (p < 0.05). A return to baseline (6.68 +/- 2.24 units) five days following the administration of ticlopidine was noted. It is concluded from this study that the acute oral administration of ticlopidine may affect neutrophil function as demonstrated by the significant increase in stimulated luminol-dependent chemiluminescence.

Adenosine Diphosphate↗
PubMedDate not supplied

The QT interval.

The effects of disease states and therapeutic drugs on the QT interval have been extensively studied in an attempt to understand the relationship between QT and the risk of torsade de pointes and sudden cardiac death. Differences in heart rate correction methods, electrocardiogram lead placement, and other internal (eg, genetic, physiologic) and external (eg, food, time of day) factors have confounded the interpretation of this relationship. A comprehensive review of the epidemiologic literature suggests that the corrected QT interval (QTc) is an important but imprecise marker of cardiovascular disease. The association between QTc prolongation and mortality has been identified in patients with cardiac disease but is unclear in patients without cardiac disease. Drug-related prolongation of QTc can clearly increase the risk of torsade de pointes, but this arrhythmia is rarely associated with a QTc of less than 500 ms. It also appears that noncardiac drugs that are associated with QTc prolongation are not identical in their proarrhythmic capacities and that increased exposure via clinically significant drug interactions is a major contributor to the liability of noncardiac drug-induced arrhythmia. Recognition of the aforementioned variables in conjunction with careful QTc measurements assists in establishing a more precise benefit-risk ratio for a specific drug therapy or for arrhythmia risk associated with various pathophysiologic or genetic states.

Animals↗