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.


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.


CONCLUSIONS
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.
Pietsch
Hubertus
H
Contrast Media Research, Bayer Schering Pharma AG, 13353 Berlin, Germany. Hubertus.Pietsch@bayerhealthcare.com
Jost
Gregor
G
Frenzel
Thomas
T
Raschke
Marian
M
Walter
Jakob
J
Schirmer
Heiko
H
Hütter
Joachim
J
Sieber
Martin A
MA
D000818:Animals; D001706:Biopsy; D001774:Blood Chemical Analysis; D002851:Chromatography, High Pressure Liquid; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016207:Cytokines / Q000097:blood; D019786:Gadolinium DTPA / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D007472:Iohexol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D028581:Lanthanoid Series Elements / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D054989:Nephrogenic Fibrosing Dermopathy / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D012871:Skin Diseases / Q000139:chemically induced*; D014057:Tomography, X-Ray Computed
D003287:Contrast Media; D016207:Cytokines; D028581:Lanthanoid Series Elements; D007472:Iohexol; C038192:iopromide; C064925:gadodiamide; D019786:Gadolinium DTPA