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M F Tweedle

Publications and source records attributed to M F Tweedle.

15 recordsLinked to original sources
PubMed1992

Dissociation of gadolinium chelates in mice: relationship to chemical characteristics.

Tissue distributions of seven 153Gd-labeled Gd chelates were determined at five residence intervals (5 min to 14 days) following intravenous administration of 0.4 mmol/kg to mice. Relationships were sought among physicochemical parameters: thermodynamic and conditional (pH 7.4) equilibrium stability constants (log K and log K'), acid dissociation rate constants (k(obs)), lipophilicity (log P), overall charge, and size (molecular weight). Size and lipophilicity did not correlate with tissue distributions. There were possible correlations between anionic charge and rapid, early renal excretion and between stability constants and long-term residual Gd deposition. Strong correlations (r greater than 0.99) were found between acid dissociation rates and long-term deposition of Gd in the whole body, liver, and femur. This is attributed to dissociation of Gd from the chelates in vivo. Acid dissociation rates may be useful in predicting dissociation of Gd from chelates in vivo.

Animals↗
PubMed1992

Quantitative dependence of MR signal intensity on tissue concentration of Gd(HP-DO3A) in the nephrectomized rat.

Cardiac-gated SE 20/224 +/- 20 MR images were obtained from nephrectomized rats before and after intravenously administering 153Gd-Gd(HP-DO3A). The concentration of Gd, [Gd], was linear in dose in myocardium, skeletal muscle, and blood. Under steady-state conditions, where d[Gd]/dt = 0, image intensities (IIN) in regions of interest were compared with the measured [Gd]. IIN was linear in myocardium at less than or equal to 0.61 mumol/g-myocardium (less than or equal to 0.5 mmol/kg dose) and in skeletal muscle at less than or equal to 0.63 mumol/g-muscle (less than or equal to 0.75 mmol/kg). Above 0.6 mumol Gd/g-tissue, IIN did not increase further. The in vivo data were consistent with measured ex vivo and in vivo relaxivities. A 29% greater slope for IIN versus [Gd] in myocardium [14,439 +/- 4350 IIN (mumol/g)] than in muscle [10,258 +/- 5,296 IIN/(mumol/g)] was attributed to a significant difference in blood content: 25% versus 2% weight blood in myocardium and skeletal muscle, respectively. Two components were apparent from plots of ex vivo 1/T1 versus [Gd] in myocardium and muscle, and only one for blood.

Animals↗
PubMed1991

Reaction of gadolinium chelates with endogenously available ions.

The extent of reaction of 153Gd-radiolabeled Gd(L) chelates with 25 mM CO23- (25 mF), PO34-, Zn2+ and Cu2+ at pH 7 was determined for L = EDTA, DTPA, DOTA, HP-DO3A, and DO3A. Gd(EDTA)- and Gd(DTPA)2- reacted (greater than 20% in 10 min) with Cu2+ and Zn2+ in the presence of PO34-. These double replacement reactions yielded precipitated GdPO4 and chelated Cu(L). Gd(HP-DO3A), Gd(DO3A) and Gd(DOTA)- were inert to reaction with all four ions at room temperature (less than or equal to 1% reaction detected). The thermodynamic binding constants of the ligands for Gd3+ and Cu2+ were found to be equal (10(20) M-1) for DO3A, while DOTA and HP-DO3A favored Gd3+ over Cu2+ by greater than or equal to 10(2) M-1. The low order of reactivity of Gd(DOTA)- and Gd(HP-DO3A) was anticipated by the binding constants, but the lack of reactivity of Gd(DO3A) is attributed to kinetic inertia. This latter property, desirable in MRI contrast agents, is promoted by the conformational stability of the tetraazacyclododecane macrocycle, which forms the backbone of the ligand. It is concluded that this class of chelates is exceptionally inert in solutions of endogenously available ions, and that thermodynamics alone is an insufficient predictor of the reactivity of the highly inert Gd complexes based on the tetraazamacrocycle.

Contrast Media↗
PubMed1990

Pharmacokinetic analysis of blood distribution of intravenously administered 153Gd-labeled Gd(DTPA)2- and 99mTc(DTPA) in rats.

Rat plasma distribution data obtained following IV administration of 99mTc(DTPA) alone or after co-administration of 99mTc(DTPA) and 153Gd-labeled Gd(DTPA)2- at 0.001, 0.1, and 1.0 mmol Gd/kg were evaluated using compartmental modeling techniques. A three-compartment open model was found to fit the data significantly better (P less than 0.01) than a two- or four-compartment open model. This model incorporates and links the plasma and urine data and includes a delay to account for the transit time through the kidneys/ureters. The two nonplasma compartments of the model were assumed to be related to rapidly and slowly equilibrating tissues. Tc(DTPA) and Gd(DTPA)2- had nearly identical pharmacokinetic profiles in plasma and the rate constants were essentially the same. No significant dose dependent pharmacokinetic differences were found for the range of Gd(DTPA)2- doses tested. Simulations of the proposed three-compartment model were used to generate concentration-time curves for each of the three compartments.

Animals↗
PubMed1990

Assays for plasma complement activation by x-ray contrast media.

Hemolytic complement activity and a C3a radioimmunoassay (RIA) were investigated for their ability to characterize contrast media (CM) with respect to complement activation. The CM tested were commercial formulations of diatrizoate, iodamide, iothalamate, ioxaglate, iohexol, and iopamidol. When plasma was exposed to CM, the hemolytic complement activity decreased and the C3a concentration increased. The C3a assay had a larger dynamic range and therefore more ability to discriminate among the CM. Using C3a data from pooled plasma or from individual donors' plasma, nonionic iopamidol (as Isovue 300) had lower complement-activating potential (P less than .005 and P greater than .05, respectively) than all of the ionic media based on diatrizoate, iothalamate, iodamide, and ioxaglate. The ranges of mean C3a values generated by saline, nonionic CM, and ionic CM were 48 to 60, 65 to 173, and 807 to 3272 ng C3a/50 microL, respectively. Complement activation was found to correlate with osmolality (r = 0.945, all media) and with molarity (r = 0.994, diatrizoates).

Complement Activation↗
PubMed1988

A predictive test for adverse reactions to contrast media. Preliminary results.

In a prospective study, whole blood samples drawn from patients prior to their being injected with contrast media were incubated with zymosan to activate the complement cascade. The samples were tested for various analytes, including C3a, thromboxane B2 (TxB2), beta thromboglobulin and platelet factor 4 (PF4). Of 207 patients receiving contrast media, only eight experienced reactions, which were mild. Levels of the platelet constituents were generally elevated in these patients. Specificity and sensitivity were 89% and 83%, respectively, for the combined TxB2 and PF4 radioimmunoassay data. Using the Wilcoxon-Mann-Whitney rank sum test, both PF4 and TxB2 were collected with RCM reactions at the R less than .05 level. Although preliminary, the results suggest that RCM reactions are predictable by the in vitro test procedures described.

Complement Activation↗
PubMed1988

Comparative chemical structure and pharmacokinetics of MRI contrast agents.

The blood clearance kinetics of five gadolinium complexes, Gd(L), were determined in rats and the results interpreted in terms of an open two-compartment pharmacokinetic model. The complexes were tested in vitro for stability in serum and in aqueous solutions of ions that they might encounter in vivo and that might be expected to react with the Gd(L) complexes to produce uncomplexed gadolinium. Reaction with serum was observed in two instances. Chemical structural differences among the chelating ligands appear to govern the overall reactivity of their Gd(L) complexes. It may be inferred from the results that a preferred structural feature of the ligand is the presence of a 12-membered 1,4,7,10-tetraaza macrocycle.

Animals↗
PubMed1985

Contrast enhanced MRI. Evaluation of a canine model of osmotic blood-brain barrier disruption.

An osmotic model of blood-brain barrier (BBB) disruption was studied by magnetic resonance (MR) imaging (0.5 T) in 17 canines. The animals were killed after imaging and the lesions confirmed on gross pathology by the presence of Evans blue dye. No accompanying cerebral edema was demonstrated on histologic examination. The disrupted BBB could be identified in only one of five control animals on unenhanced MRI, despite the use of calculated T1 and T2 images. In a second group of five animals, the area of abnormal vascular permeability was consistently demonstrated after IV injection of 0.25 mmol/kg Gd DTPA. The time course of enhancement was evaluated in four additional animals. The brain tissue concentration of the gadolinium ion responsible for the observed enhancement was determined by ion coupled plasma analysis in the last three canines. In a study of pulse techniques, spin echo sequences with both short TRs and TEs (ie, SE 500/30) and inversion recovery techniques proved to be most efficacious for the detection of contrast enhancement. However, contrast could be demonstrated on more T2 weighted sequences.

Animals↗
PubMed1978

Electronic state of heme in cytochrome oxidase III. The magnetic susceptibility of beef heart cytochrome oxidase and some of its derivatives from 7-200 K. Direct evidence for an antiferromagnetically coupled Fe (III)/Cu (II) pair.

The temperature dependence of the paramagnetic susceptibility of cytochrome oxidase and some of its derivatives has been measured from 7 to 200 K. The results obtained for the fully oxidized (resting) enzyme correspond exactly to the requirements of the model recently proposed by Palmer et al. (Palmer, G., Babcock, G. T., and Vickery, L. E. (1976) Proc. Natl. Acad. Sci. U. S. A. 73, 2206-2210) in which the enzyme possesses two magnetically isolated spin S = 1/2 centers and a spin-coupled S = 2 center. The S = 2 center paramagnetism has been interpreted as arising from a [cytochrome a33+(S = 5/2)--Cuu2+(S = 1/2)] antiferromagnetically coupled iron.copper binuclear complex of total spin S = 2 with -J greater than or equal to 200 cm-1. In addition, the wide temperature range used in the present studies has permitted an analysis of present and other available data (T less than 4K measurements) which readily accommodates results from this and other laboratories (Moss, T.H., Shapiro, E., King, T.E., Beinert, H., and Hartzell, C. R. (1978) J. Biol. Chem 253, 8072-8073) so that a fully consistent picture of the magnetic centers in cytochrome oxidase now appears to be available. Furthermore, anomalous magnetic behavior for the oxidized enzyme.cyanide complex has been interpreted in terms of an antiferromagnetic exchange interaction operating in the binuclear complex [cytochrome a33+.CN-(S = 1/2)--Cuu2+(S = 1/2)] with -J congruent to 40 cm-1. A structural model for the [cytochrome a3(3+)-bridge-CUu2+] center is advanced in which an imidazolate ion serves as the bridging ligand in a manner similar to that found in superoxide dismutase.

Animals↗