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Biomedical subjects

R B Lauffer

Publications and source records attributed to R B Lauffer.

At least 19 recordsLinked to original sources
PubMed1991

Site-specific water proton relaxation enhancement of iron(III) chelates noncovalently bound to human serum albumin.

Binding of potential blood pool and hepatobiliary paramagnetic iron(III) contrast agents, rac- and meso-Fe(5-Br-EHPG)- (iron(III) N,N'-ethylenebis [(5-bromo-2-hydroxyphenyl)glycinate]) and Fe(5-Br-HBED)- (iron(III) N,N'-bis-(5-bromo-2-hydroxybenzyl)ethylenediaminediacetic acid) to human serum albumin (HSA) has been studied using the proton relaxation enhancement (PRE) effect on solvent protons. These chelates bind avidly to multiple sites on HSA with binding constants on the order of 10(4) to 10(5) M-1. Interestingly, binding results in a decrease in the diamagnetic component of the water relaxivity due to HSA, while the expected enhancement of the paramagnetic component of water proton relaxation rates occurs due to the increase in the rotational correlation times of the protein-bound agents. These relaxation enhancements are variable, depending upon the site on the protein to which these chelates are bound, and can be as high as approximately 7 mM-1 s-1 at 5 degrees C and approximately 5 mM-1 s-1 at 37 degrees C at 20 MHz (enhancements of approximately 2-5). Change of temperature from 5 to 37 degrees C also appears to switch the relative affinities of these chelates for their primary and secondary binding sites. It is found that the important HSA binding site for the heme breakdown product, bilirubin-IX alpha, is a target for these agents and is the site of highest relaxivity for all the agents.

Bilirubin↗
PubMed1991

Targeted relaxation enhancement agents for MRI.

The design, relative merits, and initial applications of targeted relaxation enhancement agents, a new form of MRI contrast media, are briefly discussed. These agents are designed to bind reversibly to target macromolecules in a tissue of interest, thus enhancing water proton relaxation efficiency and MRI contrast. Initial applications for targeted agents include blood pool and hepatobiliary imaging.

Animals↗
PubMed1991

Iron stores and the international variation in mortality from coronary artery disease.

Possible roles for iron in coronary artery disease (CAD) have emerged, including contributions to atherogenesis and/or the vulnerability of the myocardium to ischemia/reperfusion events. The value of hepatic storage iron as a potential risk factor for CAD was evaluated independently and in combination with various lipoprotein indices using CAD mortality data from 11 countries along with available data on liver iron stores. CAD mortality rates were found to be best correlated with the liver iron-serum cholesterol product in both men (r = 0.72) and, more importantly, in both genders combined (r = 0.74). It was also found that estimated CAD incidence could be related in a non-linear fashion to iron-cholesterol values in a simple normal distribution model where all subjects above a threshold value of iron-cholesterol were assumed to have CAD. Hepatic iron values thus appear to be useful in describing the differences in CAD due to both diet (and/or culture) and sex.

Aged↗
PubMed1991

Exercise as prevention: do the health benefits derive in part from lower iron levels?

The mechanism by which exercise, a key component of modern preventative medicine, protects man from strikingly different diseases such as heart disease and cancer, is largely a mystery. It is proposed that exercise-induced reductions in iron levels, either through iron loss or enhanced iron storage, could be responsible for some of the beneficial effects. Possible roles for iron in coronary artery disease and cancer have recently emerged, particularly as a catalyst for oxygen free radical-induced tissue damage. The iron hypothesis is consistent with the graded reductions in mortality observed as a function of fitness level, and it is the first unified mechanism which can explain the reductions in both heart disease and cancer. If confirmed, preventative medicine in the future will need to include close monitoring of iron levels and, possibly, occasional blood donation for those with moderately high iron stores.

Coronary Disease↗
PubMed1991

MR imaging of blood-borne liver metastases in mice: contrast enhancement with Fe-EHPG.

To determine whether iron(III)ethylenebis-(2-hydrophenylglycine) (Fe-EHPG), a prototype hepatobiliary magnetic resonance imaging agent, can enhance the liver-to-tumor contrast-to-noise ratio (C/N) in models of liver tumors in mice, two types of cell inoculation were used: intrahepatic implantation of M5076 sarcoma and intrasplenic injection of colon tumor (C-26) or M5076 sarcoma. Significant enhancement of the liver-to-tumor C/N and/or improved visualization of small lesions was consistently observed on T1-weighted images obtained after injection of the contrast material. For intrahepatic implants, the C/N on postinjection T1-weighted images was superior to that on T1- and T2-weighted preinjection images. For the C-26 metastatic liver lesions of larger diameter (greater than 5 mm), the C/N on postinjection T1-weighted studies was superior to that on preinjection T1-weighted images but was comparable to that on preinjection T2-weighted images. However, higher C/N after administration of Fe-EHPG improved visualization of medium-sized (3-5 mm) and small (1-3-mm) metastatic lesions in both M5076 and C-26 models. These results demonstrate that MR imaging with appropriate hepatobiliary agents appears promising for early detection of liver metastases.

Animals↗
PubMed1990

Magnetic resonance contrast media: principles and progress.

The principles and current state of the art for magnetic resonance (MR) imaging contrast media are reviewed. All forms of paramagnetic and superparamagnetic MR contrast agents are covered, including discussions of their effect on MR relaxation and image intensity as well as their chemical and physiological properties.

Contrast Media↗
PubMed1990

Detection of site-specific binding and co-binding of ligands to human serum albumin using 19F NMR.

Binding and co-binding of various 19F-labeled ligands to human serum albumin (HSA) has been studied using 19F NMR. Specifically shifted resonances in slow exchange with the free resonances are detected for many of the ligands. These specifically shifted resonances can be studied to yield accurate estimates of site-specific binding constants and stoichiometries. In addition, the use of two different 19F-labeled ligands can directly reveal competition for a given site or independent binding at different sites. For instance, it is easily shown that both 5-F-L-tryptophan and 5-F-salicylic acid are capable of binding independently to two sites on HSA at the same time, without the need for any curve-fitting or assumptions. These results demonstrate that the concept of "sites" on HSA is not only useful but is necessary. The technique also reveals allosteric interactions between 5-F-L-Trp and warfarin co-bound to HSA. This technique proves to be a powerful methodology for studying ligand and drug binding to HSA that is free from some of the pitfalls associated with more traditional techniques such as equilibrium dialysis.

Allosteric Regulation↗
PubMed1988

Dynamic imaging with lanthanide chelates in normal brain: contrast due to magnetic susceptibility effects.

Using a one-dimensional rapid imaging technique, we have found that injection of lanthanide chelates such as Gd(DTPA)2- leads to a significant decrease (50%) in rat brain signal intensity at 1.45 T using T2-weighted pulse sequences; however, no effect of comparable size is observed with T1-weighted pulse sequences. The transient effect and its kinetics were followed with a temporal resolution of between 1 and 8 s. Experiments with different lanthanide chelates show that the observed decrease in signal intensity correlates with the magnetic moment of each agent but not with their longitudinal relaxivity. Three-dimensional chemical-shift resolved experiments demonstrate significant line broadening in brain during infusion with Dy(DTPA)2-. Our results show that the cause of this effect is the difference in susceptibility between the capillaries, containing the contrast agent, and the surrounding tissue. As a result of these susceptibility differences, field gradients are produced in the tissue and diffusion of water through these gradients leads to a loss of spin phase coherence and thus a decrease in signal intensity. We propose this as a new type of contrast agent mechanism in NMR. The effect and its kinetics are likely to be related to important physiological parameters such as cerebral blood volume and cerebral blood flow, and do not depend on a breakdown of the blood-brain barrier as do conventional contrast agent techniques.

Animals↗
PubMed1987

Hepatobiliary MR contrast agents: 5-substituted iron-EHPG derivatives.

A series of iron(III) ethylenebis(2-hydroxyphenyl)glycine [Fe(EHPG)]- derivatives have been examined for their role as paramagnetic hepatobiliary contrast agents for magnetic resonance (MR) imaging. The 5-substituted complexes, Fe(5-Me-EHPG)-, Fe(5-Cl-EHPG)-, and Fe(5-Br-EHPG)-, have been compared to the parent compound in rat biodistribution and MR imaging studies; correlative in vitro parameters for the complexes, including octanol-buffer partition coefficients and albumin binding affinity, have also been obtained. The three new derivatives exhibited higher degrees of lipophilicity and albumin binding affinity and varying degrees of improvement in liver-to-blood and bile-to-liver concentration ratios measured at 30 min postinjection. The 5-Cl complex had the best overall performance in terms of these tissue ratios as well as in terms of total biliary excretion. Sequential MR images of rats after administration of the complexes revealed subtle pharmacokinetic differences among the derivatives and, in general, correlated well with and complemented the biodistribution results. This study points to the sensitivity of hepatocellular uptake and excretion to simple chemical modifications and, moreover, demonstrates the importance of screening multiple derivatives to select optimal hepatobiliary MR imaging agents.

Animals↗
PubMed1987

Use of gadolinium-DTPA as a myocardial perfusion agent: potential applications and limitations for magnetic resonance imaging.

To establish the effect of the paramagnetic contrast agent gadolinium diethylenetriaminepentaacetic acid ([Gd]DTPA) on myocardial magnetic resonance relaxation parameters T1 and T2, and its relationship to myocardial perfusion, we administered [Gd] DTPA 0.2 mM/kg to two groups of dogs. Group I had severe, resting myocardial ischemia induced by coronary occlusion, followed in 2 min by [Gd]DTPA infusion and heart excision 1 min later. Group II had a variable reduction in blood flow. In Group II the coronary vasodilator dipyridamole was infused to enhance blood flow to the normal myocardium before [Gd]DTPA was given. In Group I [Gd]DTPA caused a significant difference in T1 between the normal and severely ischemic zones; changes in T1 correlated with the severity of myocardial ischemia. Although vasodilatation delivered more Gd-DTPA to the normal myocardium in Group II, the lack of further decrease in T1 suggested that it was cleared more rapidly. Thus, [Gd]DTPA permits the detection and characterization of severe, resting myocardial ischemia by magnetic resonance techniques. Using the experimental techniques described in this study, less severe flow differences caused by vasodilatation and resultant hyperemia are not detected.

Animals↗
PubMed1986

1/T1 NMRD profiles of solutions of Mn2+ and Gd3+ protein-chelate conjugates.

Bovine immunoglobulins (IgG) and bovine serum albumin (BSA) were multiply labeled with multidentate ligands, either ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA), and metal ions were inserted to form the ternary protein-ligand-ion conjugates. The NMRD profiles (the magnetic field dependence of 1/T1) of solutions of the ternary conjugates differ greatly from those of the corresponding binary ligand-metal-ion complexes, both in magnitude and functional form, exhibiting 5- to 10-fold greater relaxivities and prominent peaks near 20 MHz. The inference is that the protein-bound chelates are relatively rigidly attached to the macromolecules. The structure and metal ion affinities of these novel conjugates, as well as the relevance to contrast enhancement in NMR imaging, is discussed.

Binding Sites↗
PubMed1985

Preparation and water relaxation properties of proteins labeled with paramagnetic metal chelates.

The proteins bovine serum albumin (BSA) and bovine immunoglobulin (IgG) have been labeled with paramagnetic gadolinium (III) and manganese (II) complexes using the bifunctional chelate approach. Diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) were attached to several free amino groups on the proteins using cyclic anhydride forms of these ligands. The incorporation of the metal ions Gd+3 and Mn+2 into the chelating groups yielded highly paramagnetic proteins. The water relaxation ability (or relaxivity) of the protein-bound chelates at 20 MHz was found to be superior to that of the free metal complexes. Differences in relaxivity between the DTPA and EDTA conjugates could largely be accounted for by differences in the metal ion exposure to water. This labeling technique can be used in the preparation of intravascular NMR contrast agents (like paramagnetically-labeled human serum albumin) or target-specific agents (labeled monoclonal antibodies or fibrinogen).

Contrast Media↗
PubMed1985

Pulse sequence optimization for MR imaging using a paramagnetic hepatobiliary contrast agent.

Paramagnetic agents enhance contrast between tissues in magnetic resonance (MR) imaging by altering tissue relaxation times. The effect of these changes on MR image intensity depends in part on the choice of operator-controlled pulse sequence parameters. With the newly described paramagnetic hepatobiliary contrast agent, iron(III) ethylenebis-(2-hydroxyphenylglycine), Fe(EHPG)-, an in vivo experimental analysis of pulse sequence optimization was performed on the rat. We compared the enhancement of the liver divided by background noise, EL/N, of standard inversion-recovery (IR) and spin-echo (SE) T1-weighted pulse sequences and several pulse sequences theoretically predicted to have improved EL/N. Optimization of the echo time (TE = TEmin) gave a substantial (greater than 60%) increase in EL/N over the standard IR and SE pulse sequences. Images obtained with optimized repetition rate and inversion time gave only a slight additional improvement. Within the uncertainties of our relaxation measurements, the measured changes in EL/N with pulse sequence optimization corresponded well with theoretical predictions. With the experimental and theoretical data, the importance of using a short echo time to obtain maximal T1 contrast in contrast-enhanced MR imaging and the relative merits of optimized SE versus IR pulse sequences for contrast-enhanced MR imaging are discussed.

Animals↗
PubMed1984

Contrast agents and spectroscopic probes in NMR.

The demand for higher diagnostic specificity has led to the increased use of "foreign" agents to increase tissue contrast and/or spectroscopic sensitivity in NMR studies. The primary agents used to enhance tissue contrast in NMR imaging are paramagnetic. They cause a decrease in the proton T1 of H2O leading to enhanced signal intensity. This effect depends on the large gyromagnetic ratio of the electron, the number of unpaired electrons, the concentration of paramagnetic ions, the number of coordinated water molecules, and the rate of exchange of water. Spectroscopic enhancement has relied primarily on attempt at isotopic enrichment (usually C-13), which causes a direct increase in signal.

Carbon Isotopes↗