Efficacy and safety of lanthanoids as X-ray contrast agents.

OBJECTIVE: It has been suggested that elements from the lanthanoid (Ln) series may be well suited for use as absorbing elements in X-ray contrast agents (CA). Because gadolinium, an element of the lanthanoid series, has been identified as being possibly associated with nephrogenic systemic fibrosis (NSF), a rare but potentially severe disease, we sought to determine if other lanthanoids might possess a similar potential. MATERIALS AND METHODS: By computed tomography (CT), we compared the X-ray attenuation of all lanthanoids to that of iodine in vitro. In addition, we injected Han-Wistar rats on five consecutive days with 2.5 mmol Ln/kg bodyweight intravenously to test several Ln-DTPA-BMA complexes (praseodymium, europium, gadolinium, and holmium). Saline solution and a Ca-DTPA-BMA group served as controls. Ln concentrations in the skin and organs were determined by inductively coupled plasma mass spectrometry (ICP-MS). This method measures the total Ln content and cannot differentiate between chelated and unchelated Ln. In addition, serum cytokine levels were measured by Luminex technology. The complex stability of the Ln-DTPA-BMA complexes was also assessed in vitro. RESULTS: Lanthanoids showed up to 50% higher X-ray attenuation than iodine in CT. The highest X-ray attenuation was observed with holmium and erbium. Differences in the in vitro complex stability of Pr-, Eu-, Gd-, and Ho-DTPA-BMA complexes were observed. The complex stability differences were also reflected by differences in the concentrations in tissue of the lanthanoids in vivo. Injections of Ln complexes caused NSF-like skin lesions in rats and a rapid upregulation of pro-fibrotic and inflammatory serum cytokines. The Ca-DTPA-BMA complex did not to induce pro-fibrotic cytokines or skin lesions. Pr-DTPA-BMA appeared to be toxic; all Pr-DTPA-BMA treated animals died within the first four days of the experiment and were therefore excluded from further analyses. CONCLUSION: Lanthanoids are very well suited for higher X-ray tube voltages, particularly CT examinations. However, Ln-specific induction of NSF-like skin lesions and rapid elevation of pro-fibrotic serum cytokines levels were observed in rats following multiple administrations of high doses of Ln-DTPA-BMA complexes. The results of this animal study suggest that the stability of lanthanoid complexes may be an important consideration in evaluating the potential for in vivo safety. Furthermore the results suggest a potential of the entire class of lanthanoids to have the potential to trigger NSF-like skin lesions in rats rather than only some of the specific elements of this series.

Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C.

OBJECTIVES: Assessment of the complex stability and Gd3+ dissociation rate of all marketed gadolinium-based MRI contrast agents (GBCA) in human serum at pH 7.4 and 37 degrees C. METHODS AND RESULTS: The kinetic profiles of Gd3+ dissociation of GBCAs were determined by incubation for 15 days in human serum from healthy volunteers at a concentration of 1 mmol/L, pH 7.4, and 37 degrees C. The initial rates of Gd3+ release and the amounts of Gd3+ released after 15 days were established by HPLC-ICP-MS analysis. In an attempt to simulate the situation in patients with end-stage renal disease who often have elevated serum phosphate levels, the influence of 10 mmol/L phosphate on Gd3+ dissociation was also investigated.The GBCAs were grouped and ranked in the following order according to their stabilities in native human serum at pH 7.4 and 37 degrees C [% Gd release after 15 days and initial rate (%/d) (95% confidence interval) in brackets]. NONIONIC LINEAR GBCAS: Optimark [21 (19-22) %, 0.44 (0.40-0.51) %/d) and Omniscan [20 (17-20) %, 0.16 (0.15-0.17) %/d]. IONIC LINEAR GBCAS: Magnevist [1.9 (1.2-2.0) %, 0.16 (0.12-0.36) %/d], Multihance [1.9 (1.3-2.1) %, 0.18 (0.13-0.38) %/d], Vasovist [1.8 (1.4-1.9) %, 0.12 (0.11-0.18) %/d], and Primovist [1.1 (0.76-1.2) %, 0.07 (0.05-0.08) %/d]. MACROCYCLIC GBCAS: Gadovist, Prohance, and Dotarem (all < limit of quantification of 0.1%, <0.007%/d).In the presence of additional 10 mmol/L phosphate in serum, the initial Gd release rates of the nonionic linear GBCAs, Omniscan, and Optimark increased about 100-fold, and, after 15 days, the amount of Gd3+ released from these agents was more than 75% higher than in native serum. The initial rates found for the ionic linear GBCAs increased about 12- to 30-fold, but, despite this, increase in the initial rate, the amount of Gd3+ released after 15 days was comparable to that in native serum. The elevated phosphate level did not lead to any measurable release of Gd3+ from the 3 macrocyclic GBCAs. CONCLUSIONS: The release of Gd from all linear Gd3+ complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd3+ from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd3+ from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.

Gadolinium-based contrast agents and their potential role in the pathogenesis of nephrogenic systemic fibrosis: the role of excess ligand.

PURPOSE: To investigate the role of excess ligand present in gadolinium (Gd) -based contrast agents in the development of nephrogenic systemic fibrosis (NSF). Using a dosing regimen to simulate the exposure seen in patients with severe renal impairment, we investigated the effect of excess ligand on Gd-deposition and the depletion of endogenous ions. MATERIALS AND METHODS: Gadodiamide and gadoversetamide were formulated with 0%, 5%, and 10% excess ligand. Forty-two, healthy, male Hannover Wistar rats received daily intravenous injections of each formulation over a period of 20 days. At the end of the study, histopathological analysis of the skin was performed and the concentrations of Gd, Zn, and Cu were measured in several tissues. The levels of Zn in the urine were also measured. RESULTS: The most severe skin lesions were observed after injection of formulations containing 0% free ligand and in those animals with the highest Gd concentrations in the skin. There were no significant reductions in the levels of Zn or Cu observed in the skin; however, the levels of Zn in the urine were elevated following administration of formulations with the highest amount of excess ligand. CONCLUSION: Our findings suggest that there is an inverse correlation between the amount of excess ligand present in Gd-containing contrast agents and the amount of Gd in the tissue, and further underline the importance of the inherent stability of these agents in the development of NSF.

An efficient three-step synthesis of cyclopenta[b]pyrans via 2-donor-substituted fischer ethenylcarbenechromium complexes.

A wide range of cyclopenta[b]pyrans 4 has been synthesized in a one-pot reaction by treatment of different 2-donorsubstituted ethenylcarbenechromium complexes 2 with alkynes in THF in moderate to excellent yields (41-90 % for 14 out of 25 examples). The starting materials 2 are readily available in good to excellent yields (76-99 % for 25 out of 36 examples) by Michael addition of amines, alcohols and thiols, respectively, to the corresponding alkynylcarbenechromium complexes 1. Due to their 10 pi-electrons in a cross-conjugated bicyclic system, cyclopenta[b]pyrans have been termed pseudoazulenes, as they indeed have similar UV/Vis-spectroscopic properties.

New contrast media designed for x-ray energy subtraction imaging in digital mammography.

RATIONALE AND OBJECTIVES: In contrast-enhanced dual-energy subtraction imaging 2 images acquired postcontrast media administration at different energies are subtracted to highlight structures hidden in the absence of contrast media. X-ray spectra of the newly developed digital full-field mammography units (GE Senographe 2000 D) are dominated by the emission lines of the Mo or Rh anodes. The K-edge of Zirconium (Zr) is flanked by these 2 emission lines. Thus, the attenuation of Zr should experience a pronounced change of attenuation in parallel with a change of anodes. Under clinically relevant conditions, the contrasting behavior of Zr should be compared with that of other elements having K-edge energies outside the window spanned by the 2 anode emission lines. METHODS: Solutions containing the contrasting elements Br, Y, Zr, I, and Gd were investigated for dual-energy subtraction in digital mammography with the 2 anode/filter settings (Mo/Mo and Rh/Rh). These solutions were investigated in phantom studies in the energy range conventionally used in mammography. Additionally, the contrasting behavior of Zr and I was compared in an in vivo study in rats. RESULTS: The sweeping over the K-edge by alternating between the Mo and Rh anodes increases the detection of Zr in energy subtraction imaging at constant high voltage. This procedure does not lead to sufficient contrast enhancement for iodine-based contrast media which become detectable by increasing the high voltage to 40-49 kV. CONCLUSION: The instrumental and physical data outlined predestine Zr as contrasting element with a high potential for energy subtraction imaging in digital mammography in the energy range conventionally applied.

Highly Substituted Spiro[4.4]nonatrienes from a ß-Amino-Substituted α,ß-Unsaturated Fischer Carbene Complex and Three Molecules of an Arylalkyne.

A novel mode of reaction towards arylethynes is shown by the ß-trimethylsilyl-substituted α,ß-unsaturated Fischer carbene complexes 1. A mixture of the isomeric, highly substituted spiro[4.4]nonatrienes 2 and 3 is formed by the formal insertion of three alkyne molecules and subsequent cyclization (see scheme). Such selective triple insertions of alkynes into ethenylcarbene complexes have not been previously observed.