William P. Cacheris

The relationship between thermodynamics and the toxicity of gadolinium complexes

The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial. Release of Gd3+ from the complex is responsible for the toxicity associated with gadolinium complexes; this release appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LD50 values for four Gd complexes, all become lethally toxic when they release precisely the same quantity of Gd3+, and by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency. Finally, this hypothesis predicts that subtle changes in formulation can further enhance the intrinsic safety of these complexes.

Emulsions of paramagnetic contrast agents for magnetic resonance imaging (MRI).

Emulsions of paramagnetic contrast agents, and processes of making and using them are disclosed. The emulsions contain water, a dispersed oil phase and a complex of a paramagnetic metal ion and an organic chelator having a C10 -C30 unsaturated aliphatic group. The emulsions are very stable and therapeutically acceptable for intravenous administration to enhance MRI.

Paramagnetic complexes of n-alkyl-n-hydroxylamides of organic acids and emulsions containing same for magnetic resonance imaging (mri)

Emulsions of paramagnetic contrast agents, and processes of making and using them are disclosed. The emulsions contain water, a dispersed oil phase and a complex of a paramagnetic metal ion and an organic acid chelator, for example DTPA (diethylenetriaminepentaacetic acid), having a C10 -C30 saturated aliphatic group and an hydroxyl group bonded to the nitrogen atom. The emulsions are very stable and therapeutically acceptable for intravenous administration to enhance MRI imaging.