Perflubron emulsion (AF0144) augments harvesting of autologous blood: a phase II study in cardiac surgery.

Objective: To assess tolerance and preliminary efficacy of a perfluorocarbon emulsion (AF0144) used with acute normovolemic hemodilution to reduce allogeneic blood transfusion for patients undergoing coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB).

Design: Controlled, single-blind, parallel-group phase II dose escalation trial.

Setting: Single-institution university medical center.

Randomized safety studies of intravenous perflubron emulsion. II. Effects on immune function in healthy volunteers.

Particle size distribution is a major determinant of particle clearance by the mononuclear phagocytic system and the potential for concomitant activation of resident macrophages. To test the safety of a second-generation perflubron-based emulsion (60% perfluorocarbon [PFC] wt/vol; Oxygent [Alliance Pharmaceutical Corp., San Diego, CA]) with a small mean particle size, two parallel, randomized, double-blinded, placebo-controlled studies were conducted in 48 healthy volunteers (n = 24 per study).

Randomized safety studies of intravenous perflubron emulsion. I. Effects on coagulation function in healthy volunteers.

Previous perfluorocarbon (PFC) emulsions have been associated with transient adverse events (i.e., platelet activation, decreased platelet count, febrile responses, changes in hemodynamic function).

A pilot study of the effects of a perflubron emulsion, AF 0104, on mixed venous oxygen tension in anesthetized surgical patients.

A pilot study of a perfluorochemical (PFC) emulsion was undertaken to determine whether administration of a perflubron emulsion could result in measurable changes in mixed venous oxygen tension. Seven adult surgical patients received a 0.9-g PFC/kg intravenous dose of perflubron emulsion after acute normovolemic hemodilution (ANH).

Preclinical and clinical studies on lymph node imaging using perflubron emulsion.

A perflubron emulsion is being developed as a contrast agent to enhance lymph nodes on computed tomography (CT) images. The emulsion is administered by percutaneous injection into the drainage field of the lymph nodes to be imaged. A series of preclinical studies was conducted to investigate the efficacy of the perflubron emulsion for enhancement of lymph nodes on CT images.

Some benzyl-substituted imidazoles, triazoles, tetrazoles, pyridinethiones, and structural relatives as multisubstrate inhibitors of dopamine beta-hydroxylase. 4. Structure-activity relationships at the copper binding site.

Structure-activity relationships (SAR) were determined for novel multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.

SK&F 89124, a potent and selective agonist at prejunctional dopamine receptors.

SK&F 89124 (4-[2-(N,N-di-n-propylamino)ethyl]-7-hydroxy-2(3H) indolone) can be considered as a derivative of N,N-di-n-propyldopamine (DPDA) in which the meta-hydroxyl is replaced by a cyclic amide function. SK&F 89124 is at least one order of magnitude more potent than DPDA as an agonist at peripheral inhibitory prejunctional dopamine receptors (DA2 receptors) in the isolated perfused rabbit ear artery. A potent agonist action of SK&F 89124 at the DA2 receptor can also be demonstrated by inhibition of radioactive overflow from prelabelled canine coronary artery or saphenous vein, and in the anesthetized dog as an inhibition of the tachycardia induced by cardioaccelerator nerve stimulation or the increase in hind-limb perfusion pressure induced by stimulation of the lumbar sympathetic chain.

Effect of amino acid deprivation on initiation of protein synthesis in rat hepatocytes.

Conditions were defined for maintaining optimal protein synthetic activity in suspensions of freshly isolated rat hepatocytes. Under these conditions, isolated hepatocytes exhibited rates of protein synthesis and levels of polysomal aggregation equivalent to those observed in vivo and in perfused liver. Deprivation of total amino acids or single, essential amino acids resulted in a rapid decrease in the rate of protein synthesis, which was readily reversed by readdition of the deficient amino acid(s).

Initiation of protein synthesis in a cell-free system prepared from rat hepatocytes.

A cell-free system, which maintained a linear rate of protein synthesis for up to 20 min of incubation, was prepared from isolated rat hepatocytes. The rate of protein synthesis in the cell-free system was approximately 20% of the rate obtained in isolated hepatocytes or perfused liver. More than 70% of total protein synthesis in the cell-free system was due to reinitiation, as indicated by addition of inhibitors of initiation, i.

Inhibitors of dopamine beta-hydroxylase. 3. Some 1-(pyridylmethyl)imidazole-2-thiones.

The 1-benzylimidazole-2-thione moiety has been previously shown by Kruse et al. to be broadly associated with dopamine beta-hydroxylase (DBH) inhibitory activity both in vitro and in vivo in spontaneously hypertensive rats (SHR). An extension of structure-activity studies to 1-(pyridylmethyl)- and 1-(oxypyridylmethyl)imidazole-2-thiones is reported here in an attempt to exploit the pH differential that exists across the chromaffin vesicle membrane.

Synthesis, conformation, and dopaminergic activity of 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines.

To probe the suggestion that D-1 (DA1) dopamine receptors might possess an accessory pi-binding site in a location complementary to a suitably oriented aromatic ring (i.e., in an axial orientation approximately orthogonal to the catechol nucleus) in agonists such as 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol (1) and 3',4'-dihydroxynomifensine (2) that are selective for this subtype, cis- and trans-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine-6,7-diol were prepared.

Synthesis and evaluation of non-catechol D-1 and D-2 dopamine receptor agonists: benzimidazol-2-one, benzoxazol-2-one, and the highly potent benzothiazol-2-one 7-ethylamines.

Our interest in identifying D-1 and D-2 dopamine receptor agonists that are not catechols led us to extend previous studies with oxindoles by investigating analogues of dopamine, N,N-dipropyldopamine, m-tyramine, N,N-dipropyl-m-tyramine, and epinine in which the m-hydroxyl is replaced by the NH portion of a thiazol-2-one, oxazol-2-one, or imidazol-2-one group fused to the 2,3-position. These compounds were evaluated for their affinity and agonist activity at D-1 and D-2 receptors by using in vitro assays. Replacement of the m-hydroxy in N,N-dipropyldopamine with the thiazol-2-one group resulted in a dramatic increase in D-2 receptor affinity and activity compared to that of N,N-dipropyldopamine itself or that of the corresponding oxindole, 1.

Multisubstrate inhibitors of dopamine beta-hydroxylase. 2. Structure-activity relationships at the phenethylamine binding site.

1-Aralkylimidazole-2-thiones have been shown to be potent multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.

Multisubstrate inhibitors of dopamine beta-hydroxylase. 1. Some 1-phenyl and 1-phenyl-bridged derivatives of imidazole-2-thione.

The synthesis and characterization of some 1-(phenylalkyl)imidazole-2-thiones as a novel class of "multisubstrate" inhibitors of dopamine beta-hydroxylase (DBH) are described. These inhibitors incorporate structural features that resemble both tyramine and oxygen substrates, and as evidenced by steady-state kinetics, they appear to bind both the phenethylamine binding site and the active site copper atom(s) in DBH. A series of structural congeners that incorporate different bridging chain lengths between the phenyl ring (dopamine mimic) and the imidazole-2-thione group (oxygen mimic) define the optimum distance for inhibitory potency and the likely intersite distance in the DBH active site.

Synthesis and renal vasodilator activity of some dopamine agonist 1-aryl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diols: halogen and methyl analogues of fenoldopam.

Certain 6-halo-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines were found to be potent D-1 dopamine agonists. The 1-(4-hydroxyphenyl) analogues did not have central nervous system activity because their high polarity inhibited entry into the brain. However, these compounds were potent renal vasodilators.

Synthesis and dopaminergic binding of 2-aryldopamine analogues: phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes.

A series of 2-aryldopamine analogues were synthesized and evaluated for their effects on D1 and D2 dopamine receptors. The 2-phenyldopamine and 6-phenylbenzazepine analogues exhibited weak binding to both D1 and D2 receptors. The 9-(aminomethyl)fluorenes also exhibited weak D2 binding; however, 2,5,6-trihydroxy-9H-fluorene-9-methanamine (4b) exhibited D1 binding comparable to apomorphine.

Synthesis and dopaminergic activity of some halogenated mono- and dihydroxylated 2-aminotetralins.

In a series of 7,8-dihydroxy-1-phenyltetrahydro-3-benzazepine dopamine receptor agonists introduction of a chloro or fluoro substituent into the 6-position increases dopaminergic potency. Also, in this series replacement of the 7-hydroxyl group with a halogen results in inversion of activity from dopamine receptor agonist to antagonist. The present study was aimed at exploring the possibility that the structure-activity observations in the 3-benzazepine series of dopaminergic agents might be extrapolated to another class of dopamine receptor agonists, the 2-aminotetralins.

Regulation of agonist and antagonist binding to striatal D-1 dopamine receptors: studies using the selective D-1 antagonist [3H]SK&F R-83566.

The potent and D-1 versus D-2 selective dopamine receptor antagonist, SK&F R-83566, was radiolabelled with tritium and was used as a radioligand for examination of D-1 receptors in rat striatum. Binding of the radioligand was stereoselective, saturable and reversible. In homogenates of rat striatum, nonspecific binding of the radioligand was less than 5% of total binding, the KD was 1.

Dopamine receptor agonist activity of some 5-(2-aminoethyl)carbostyril derivatives.

The potency of beta-adrenoreceptor agonists, e.g., isoproterenol, is strikingly increased by substitution of the meta catecholic hydroxyl group with the NH group of a carbostyril system.

Direct effect of insulin on albumin gene expression in primary cultures of rat hepatocytes.

The purpose of this study was to identify a cell culture system in which the role of insulin in regulating albumin gene expression could be investigated. The system selected was rat hepatocytes maintained in primary culture in a chemically defined, serum-free medium. Under control conditions albumin secretion was nearly the same as the rate recorded in vivo and in perfused liver and was reasonably well maintained during 8 days of culture.

Binding of a novel dopaminergic agonist radioligand [3H]-fenoldopam (SKF 82526) to D-1 receptors in rat striatum.

Fenoldopam (SKF 82526), a dopamine agonist which exhibits D-1 receptor subtype selectivity, was evaluated as a radioligand for this receptor subtype. In saturation studies in rat striatal membrane preparations, [3H]-fenoldopam appeared to label a single binding site with a KD of 2.3 +/- 0.

Protein synthesis versus energy state in contracting muscles of perfused rat hindlimb.

The goal of these studies was to evaluate acute changes in protein metabolism in skeletal muscle in response to contractile activity. Rates of protein synthesis were measured by following L-[U-14C]phenylalanine incorporation into protein in muscles of the perfused rat hindlimb at rest, during 10 min of maximal isometric muscle contractions, and during 10 min of recovery. Synthesis measurements were carried out under conditions that ensured that the specific radioactivity of the tRNA-bound precursor amino acid was equal to that of extracellular phenylalanine.

Effect of halothane on synthesis and secretion of liver proteins.

The effect of halothane on synthesis of retained and secreted proteins was investigated using isolated perfused rat livers. Anesthetic exposure rapidly inhibited synthesis of total liver proteins in a dose-dependent manner by a mechanism which appeared to involve reduced rates of both peptide chain initiation and elongation. While halothane concentrations comparable to the clinical dose resulted in small changes in protein metabolism, higher concentrations (4%) of the anesthetic had marked effects.