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Biomedical subjects

R J Boudreau

Publications and source records attributed to R J Boudreau.

10 recordsLinked to original sources
PubMed1992

Liver transplant rejection and cholestasis: comparison of technetium 99m-diisopropyl iminodiacetic acid hepatobiliary imaging with liver biopsy.

To determine whether the scintigraphic evaluation of technetium-99m diisopropyl iminodiacetic acid (DISIDA) uptake and excretion can distinguish among liver transplant patients with biopsy evidence for rejection, cholestasis or neither condition, we reviewed scintigrams and biopsies in 36 patients. There were 76 scintigrams with corresponding biopsies. Uptake and excretion were graded from image data on scales reflecting normal through severely abnormal values. Biopsies were evaluated for findings of cholestasis and rejection. The majority of scintigrams demonstrated normal uptake (60/75, 80%) and delayed excretion (65/76, 85%), which was most marked immediately after transplantation. One-way analysis of variance showed that the mean excretion values significantly differed between patients with normal biopsies and those with cholestasis and/or rejection (P = 0.0003). However, mean uptake scores demonstrated no statistically significant difference between these two groups of patients (P = 0.1). These findings suggest that 99mTc-DISIDA scintigraphy can differentiate between transplants with and without rejection/cholestasis but not between rejection and cholestasis. If 99mTc-DISIDA excretion is normal, rejection and cholestasis are unlikely.

Cholestasis↗
PubMed1992

Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane: potential radiotracer for mapping central cholinergic innervation in vitro.

Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane, 5 (4-HIPP), was synthesized and evaluated as a simple vesamicol-like radiotracer for mapping cholinergic pathways in the brain. Both enantiomers of 5 exhibit significant accumulation (approx. 2% of injected dose) and prolonged retention (t1/2 greater than 3 h) within the rat brain. The accumulation of radioiodinated 5 in the rat brain was reduced by up to 70% in the presence of vesamicol and its analogs. The levorotary isomer (-)-4-[123I]HIPP exhibits significant accumulation in the monkey brain, with a half-life of about 9 h. Radioiodinated 5 may therefore be a useful tool for studying cholinergic pathways in the brain.

Animals↗
PubMed1992

Aerosol scintigraphy in the assessment of therapy for cystic fibrosis.

Thirteen patients with cystic fibrosis (aged 11 to 32 years) who were hospitalized for exacerbation and who had sputum cultures positive for Pseudomonas organisms were treated initially for 4 days with bronchodilators and physiotherapy followed by the addition of antibiotic (14 days, n = 8) or placebo (14 days, n = 4; 7 days, n = 1). Tc-99m DTPA aerosol scintigraphy was performed on the day before bronchodilators and physiotherapy, on the day before antibiotic or placebo, and on the day after completion of antibiotic or placebo therapy. Scintigrams were evaluated for change in the number of nonventilated segments and change in the number of bronchial deposits of aerosol. Sixty-nine percent of patients showed improvement after bronchodilators and physiotherapy alone. Sixty-two percent showed further improvement after antibiotic or placebo was added; this improvement was independent of whether antibiotic or placebo was administered (P greater than 0.1). These aerosol scintigraphy results failed to demonstrate that the effectiveness of bronchodilators and physiotherapy is enhanced by antibiotics in the treatment of cystic fibrosis exacerbations.

Adult↗
PubMed1992

Computer-aided radiopharmaceutical design.

The ultimate goal of a QSAR analysis is prediction, which depends on the elaboration of the most appropriate set of molecular descriptors. As such, molecular description is the nucleus of QSAR and in the absence of exhaustive molecular description, rational drug design may be greatly impeded. As previously discussed, computational methods such as quantum mechanics and molecular mechanics provide molecular description at a fundamental level which then enhances the descriptive capability and predictive power of a QSAR analysis. In recognition of these capabilities, semi-empirical molecular orbital methods and molecular mechanics now have been incorporated into or interphased with QSAR programs. Such integrated packages are being successfully used in computer-aided molecular modeling. Computer-aided molecular modeling can provide the three-dimensional structure of a molecule, its chemical and physical characteristics, comparisons of structures of different molecules, and visualization of complexes formed between them. From the foregoing, predictions may be made about how related new molecules may function. Thus, the combination of quantum and/or molecular mechanics and QSAR provides a formidable weapon in the chemist's armamentarium. The molecular modeling approaches are certainly more practical to use than physicochemical methods. They also provide electronic and thermodynamic data that are not available from x-ray crystallographic data. Of course, these techniques are not confined to radiopharmaceutical development and they also could aid in the development of contrast agents for radiography or magnetic resonance imaging. We believe that as computational resources and capabilities increase over the next decade, computer-aided drug design will become a standard procedure in all drug development laboratories.

Binding Sites↗
PubMed1991

Molecular determinants in the bioactivation of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Nineteen analogs of the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been used as probes to study the structural parameters that influence MAO-catalyzed oxidation. In this study, the efficiency of enzyme-catalyzed substrate oxidation was found to be unrelated to parameters such as the ionization potential, dipole moment, net atomic charge at C5 and the dihedral angle between the phenyl ring and the tetrahydropyridine moiety. Conformational analysis revealed that substitution at the C2' position of MPTP yields atropisomers. It is suggested that one of these atropisomers would be either inactive or substantially less active than the other. Therefore, the relative oxidative efficiency and toxicity of these compounds reported earlier may have been significantly underestimated. Based on the conformational analysis and other data, a rudimentary model of the MAO substrate site has been developed which partially explains the substrate specificities of MAO A and MAO B. Each substrate binding site can be divided into two regions, (a) an amine-binding pocket (for the tetrahydropyridine moiety), and (b) a 'bulky substituent' region (for the phenyl group and its substituents). The length of the substrate binding site (measured along the long axis of MPTP) is approximately 8.5 A, and the width of the 'amine-binding' pocket is approximately 2.5 A (from C3 to C5). The 'bulky substituent' region contains a central area for binding the phenyl group of MPTP. This central area is flanked by two hydrophobic pockets, P2' and P3'. In MAO A, the pocket P2'-A is oriented 45-135 degrees relative to the plane of the tetrahydropyridine moiety, with a radius of 3.1 A from C2' of the phenyl ring. The radius of a similar but smaller pocket, P2'-B, in MAO B, is approximately 2.7 A. In MAO B, the pocket P3'-B (radius 2.36 A from C3') is larger than a similar pocket P3'-A (radius 1.70 A from C3') in MAO A. The foregoing characterization suggests that differences in the size and topography of both of the substituent pockets play an important role in determining the substrate specificities of these two isozymes.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Correlation of technetium-99m-DISIDA hepatobiliary studies with biopsies in liver transplant patients.

We compared 76 99mTc-DISIDA hepatobiliary studies with corresponding liver biopsies in 36 liver transplant patients to determine the histopathologic abnormalities that corresponded to scintigraphic abnormalities in uptake and excretion. Uptake was judged normal if the cardiac blood pool was barely visible or invisible on the ten minute image. Excretion was judged normal if images subsequent to the 15-min image showed a subjectively normal rate of decreasing parenchymal intensity. Biopsies were graded subjectively for hepatocyte damage and for findings of cholestasis. Uptake criteria were successful in differentiating high from low hepatocyte damage scores (p less than 0.0001), and excretion criteria were successful in differentiating high from low cholestasis scores (p = 0.002), while uptake criteria were not capable of differentiating high from low cholestasis scores, nor were excretion criteria capable of differentiating high from low hepatocyte damage scores (p's greater than 0.05). These results suggest that scintigraphy can distinguish intrahepatic cholestasis from pure hepatocyte damage.

Biopsy, Needle↗
PubMed1979

Cardiac edema in dogs: distribution of renal blood flow and glomerular filtrate.

The injection of Freund's adjuvant into the pericardial sac of 29 dogs resulted in chronic pericardial tamponade with persistent sodium retention. Micropuncture, clearance, and radioactive microsphere experiments were initiated 6--13 days after pericardial injection and 60 min after pericardiocentesis. Pericardiocentesis increased sodium excretion (from 12.2 to 41.3 microequiv./min) and mean arterial pressure (+ 20 mmHg (1 mmHg = 133.322 Pa)). Central venous pressure decreased 6.5 mmHg, as did hematocrit (from 45.7 to 39.8%) and plasma protein concentration (from 5.88 to 5.15 g%). Pericardiocentesis had no significant effect on renal blood flow (RBF), nor plasma flow. Redistribution of glomerular filtrate was suggested by the observation that superficial nephron glomerular filtration rate increased (from 91 to 108 nL/min) while glomerular filtration rate remained unaltered. Determination of intrarenal distribution of RBF revealed that cortical blood flow also distributed superficially. A significant increase in the fraction of RBF perfusing zone 1 (outer cortex) and a decrease in fractional perfusion of zones 2, 3 and 4 (juxtamedullary cortex) were observed in each experiment following pericardiocentesis. RBF distribution examined in a series of six animals prior to and during the development of pericardial tamponade showed the opposite effect. These results indicate that pericardiocentesis causes redistribution of both glomerular filtrate and RBF to superficial nephrons. The development of pericardial tamponade was associated with increased fractional juxtamedullary blood flow. These changes may have been the result of altered blood pressure, hematocrit, plasma protein concentration, or altered renal resistance.

Animals↗
PubMed1975

Activation of 3',5'-cyclic adenosine monophosphate phosphodiesterase by calcium ion and a protein activator.

3',5'-CAMP phosphodiesterase was partially purified from bovine cerebral cortex. A heat-stable activating factor was separated from the enzyme by chromatography on DEAE-cellulose. The enzyme in crude ammonium sulfate fractions was stimulated by 5 mM CaCl2. This stimulation was reversed by the calcium chelator EGTA. The main phosphodiesterase peak obtained by DEAE-cellulose chromatography was not stimulated by Ca2+. Upon addition of column effluent containing a heat stable factor, Ca2+ activation was restored. Protein activator was inactive when endogenous contaminating Ca2+ was complexed with EGTA. It was concluded that activation of phosphodiesterase requires the presence of both activator and Ca1+. From an analysis of activation of cGMP hydrolysis a kinetic model for the interaction of Ca2+ and protein activator with the phosphodiesterase was developed. Heterotropic cooperativity between the binding of Ca2+ and protein activator to the phosphodiesterase was observed, i.e., Ca1+ decreased the apparent dissociation constant for protein activator and protein activator decreased the apparent dissociation constant for Ca2+.

Animals↗
PubMed1975

The effect of Ca++ on cyclic nucleotide phosphodiesterases of superior cervical ganglion.

Cyclic nucleotide phosphodiesterase was examined in canine and bovine superior cervical ganglia. Activity in crude supernatant fractions was only slightly stimulated by Ca++ despite the presence of protein activating factor. Three forms of phosphodiesterase were resolved from bovine ganglia supernatant extracts by chromatography on DEAE-cellulose. The first enzyme eluted, (DI), was almost completely specific for cyclic GMP, while the other two (DII and DIII), hydrolyzed both cyclic AMP and cyclic GMP; all were free of heat-stable protein activator. Each enzyme was inhibited by low concentrations of Ca++ in the assay medium. Inhibition by Ca++ was reversed by addition of protein activator, but activity did not increase above the control level. Cyclic AMP hydrolysis by enzyme DII was stimulated by micromolar concentrations of cyclic GMP. This stimulation was reduced by Ca++ unless protein activator was present.

3',5'-Cyclic-AMP Phosphodiesterases↗