ABSTRACT
Site-directed contrast enhancement of angiogenic vessels in vivo was demonstrated using antibody targeting of an MRI contrast agent to the alpha(v)beta(3) integrin, a molecular marker characteristic of angiogenic endothelium. The agent was tested in a rabbit corneal micropocket model, in which neovasculature is induced in the cornea using basic fibroblast growth factor. The targeted contrast agent consists of Gd-perfluorocarbon nanoparticles linked to alpha(v)beta(3) integrin antibody DM101. The animal group receiving the targeted contrast agent displayed a 25% increase in the average MR signal intensity after 90 min. Control groups in which the nanoparticles are either used alone, linked to an isotype-matched antibody, or linked to DM101 and administered following receptor blocking did not display MR contrast enhancement at similar dose levels. These findings indicate that the antibody-targeted agent enhances MR signal intensity in the capillary bed in a corneal micropocket model of angiogenesis, and is selectively retained within the angiogenic region via specific interaction with the alpha(v)beta(3) epitope.
Subject(s)
Contrast Media/administration & dosage , Corneal Neovascularization/diagnosis , Fluorocarbons , Image Enhancement/methods , Magnetic Resonance Angiography/methods , Receptors, Vitronectin/metabolism , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/metabolism , Antibody Specificity , Biotinylation , Contrast Media/chemistry , Cornea/blood supply , Cornea/pathology , Corneal Neovascularization/chemically induced , Corneal Neovascularization/metabolism , Corneal Neovascularization/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Fibroblast Growth Factor 2 , Fluorocarbons/administration & dosage , Gadolinium/administration & dosage , Immunohistochemistry , Injections, Intravenous , Microspheres , Neovascularization, Pathologic/chemically induced , Neovascularization, Pathologic/diagnosis , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Rabbits , Receptors, Vitronectin/immunology , Thrombomodulin/metabolismABSTRACT
We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol - 5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AII) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT1 receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contraction of rabbit aortic rings by AII was antagonized by SC-52458 in a competitive and reversible manner (pA2 of 8.18). SC-52458 had no effect on the activity of angiotensin converting enzyme (ACE) or renin in vitro. In normotensive rats, administration of SC-52458, either intravenously (i.v.) or by gavage, inhibited the pressor response to AII. Daily treatment with SC-52458 at 20, 30, and 50 mg/kg by gavage for 4 days decreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-deficient dogs demonstrated that oral administration of SC-52458 decreased BP and that this activity was correlated with significant plasma levels of the compound. SC-52458 is an orally active, competitive AT1-receptor antagonist with antihypertensive properties.
Subject(s)
Angiotensin II/antagonists & inhibitors , Angiotensin Receptor Antagonists , Blood Pressure/drug effects , Pyridines/pharmacology , Tetrazoles/pharmacology , Administration, Oral , Adrenal Cortex/drug effects , Adrenal Cortex/metabolism , Angiotensin II/metabolism , Angiotensin II/pharmacology , Animals , Binding Sites , Female , Heart Rate/drug effects , Hypertension/drug therapy , Hypertension/physiopathology , In Vitro Techniques , Male , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Peptidyl-Dipeptidase A/metabolism , Rabbits , Rats , Rats, Inbred SHR , Receptors, Angiotensin/metabolism , Renin/blood , Uterus/metabolismABSTRACT
We completed a comprehensive factor analysis of the full MMPI item pool by using recent advances in computational facilities. Nearly 20,000 MMPI protocols were collected for the analysis, however, we discarded invalid records and protocols with more than 50 missing items. Analyses were computed on a developmental sample of 5,506 subjects and a cross-validation sample of 5,632. Twenty-one replicated factors were found by using an orthogonal varimax solution. The rotated factors were submitted to several experts on MMPI for factor naming. The consensus obtained on the item factors suggests that this analysis provides an unambiguous picture of the major content dimensions in the MMPI item pool.
