Mutagenicity assessment of two potential impurities in preparations of 5-amino-2,4,6 triiodoisophthalic acid, a key intermediate in the synthesis of the iodinated contrast agent iopamidol.

5-Aminoisophthalic acid and 5-nitroisophthalic acid (5-NIPA) are potential impurities in preparations of 5-amino-2,4,6-triiodoisophthalic acid, which is a key intermediate in the synthesis of the iodinated contrast agent iopamidol. We have studied their mutagenicity in silico (quantitative structure-activity relationships, QSAR) and by the bacterial reverse mutation assay (Ames test). First, the compounds were screened with the tools Derek Nexus™ and Leadscope®. Both compounds were flagged as potentially mutagenic (class 3 under ICH M7). However, contrary to the in silico prediction, neither chemical was mutagenic in the Ames test (plate incorporation method) with or without S9 metabolic activation.

Gadolinium retention in a rat model of subtotal renal failure: are there differences among macrocyclic GBCAs?

BACKGROUND: Gd levels are higher in tissues of animals with compromised renal function, but studies to compare levels after exposure to different macrocyclic gadolinium-based contrast agents (GBCAs) are lacking. We compared Gd levels in tissues of subtotally nephrectomised (SN) rats after repeated exposure to macrocyclic GBCAs. METHODS: Sprague-Dawley SN male rats (19 per group) received 16 injections of gadoteridol, gadobutrol, or gadoterate meglumine at 0.6 mmol Gd/kg 4 times/weeks over 4 weeks. A control group of healthy male rats (n = 10) received gadoteridol at the same dosage. Plasma urea and creatinine levels were monitored. Blood, cerebrum, cerebellum, liver, femur, kidney(s), skin and peripheral nerves were harvested for Gd determination by inductively coupled plasma-mass spectrometry at 28 and 56 days after the end of treatment. RESULTS: Plasma urea and creatinine levels were roughly twofold higher in SN rats than in healthy rats at all timepoints. At day 28, Gd levels in the peripheral nerves of gadobutrol- or gadoterate-treated SN animals were 5.4 or 7.2 times higher than in gadoteridol-treated animals (p < 0.001). Higher Gd levels after administration of gadobutrol or gadoterate versus gadoteridol were also determined in kidneys (p ≤ 0.002), cerebrum (p ≤ 0.001), cerebellum (p ≤ 0.003), skin (p ≥ 0.244), liver (p ≥ 0.053), and femur (p ≥ 0.271). At day 56, lower Gd levels were determined both in SN and healthy rats for all GBCAs and tissues, except the femur. CONCLUSIONS: Gd tissue levels were lower following gadoteridol exposure than following gadobutrol or gadoterate exposure.

Gadolinium Clearance in the First 5 Weeks After Repeated Intravenous Administration of Gadoteridol, Gadoterate Meglumine, and Gadobutrol to rats.

BACKGROUND: Studies of gadolinium (Gd) clearance from animals in the first weeks after administration of gadolinium-based contrast agents (GBCAs) have previously looked at solitary timepoints only. However, this does not give information on differences between GBCAs and between organs in terms of Gd elimination kinetics. PURPOSE: To compare Gd levels in rat cerebellum, cerebrum, skin, and blood at 1, 2, 3, and 5 weeks after repeated administration of macrocyclic GBCAs. STUDY TYPE: Prospective. ANIMAL MODEL: One hundred eighty male Sprague-Dawley rats randomized to three groups (n = 60/group), received intravenous administrations of gadoteridol, gadoterate meglumine, or gadobutrol (0.6 mmol/kg for each) four times/week for 5 consecutive weeks. Rats were sacrificed after washout periods of 1, 2, 3, or 5 weeks. FIELD STRENGTH/SEQUENCE: Not applicable. ASSESSMENT: Cerebellum, cerebrum, skin, and blood were harvested for Gd determination by inductively coupled plasma-mass spectrometry (15 animals/group/all timepoints). STATISTICAL TESTS: Anova and Dunnett's test (data with homogeneous variances and normal distribution). Kruskal-Wallis and Wilcoxon's rank sum tests (data showing nonhomogeneous variances or a non-normal distribution, significance levels: P < 0.05, P < 0.01, and P < 0.001). RESULTS: Gd levels in cerebellum, cerebrum, and skin were significantly lower after gadoteridol than after gadoterate and gadobutrol at all timepoints. Mean cerebellum Gd concentrations after gadoteridol, gadoterate, and gadobutrol decreased from 0.693, 0.878, and 1.011 nmol Gd/g at 1 week to 0.144, 0.282, and 0.297 nmol Gd/g at 5 weeks after injection. Similar findings were noted for cerebrum and skin. Conversely, significantly higher Gd levels were noted in blood after gadoteridol compared to gadobutrol at 1, 2, and 3 weeks and compared to gadoterate at all timepoints. DATA CONCLUSION: Gadoteridol is eliminated more rapidly from rat cerebellum, cerebrum, and skin compared to gadoterate and gadobutrol in the first 5 weeks after administration, resulting in lower levels of retained Gd in these tissues. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 5.

Pharmaceutical Development and Safety Evaluation of a GMP-Grade Fucoidan for Molecular Diagnosis of Cardiovascular Diseases.

The adhesion molecule P-selectin is present on the cell surface of both activated endothelium and activated platelets. The present study describes the pharmaceutical development, safety evaluation, and preclinical efficacy of a micro-dosed radiotracer. The macromolecular nanoscale assembly consisted of a natural compound made of a sulfated fucose-rich polysaccharides (fucoidan) and a radionuclide (technetium-99m) for the detection of P-selectin expression in cardiovascular diseases. After extraction and fractionation from brown seaweeds, the good manufacturing practice (GMP) production of a low molecular weight (LMW) fucoidan of 7 kDa was achieved and full physicochemical characterization was performed. The regulatory toxicology study in rats of the GMP batch of LMW fucoidan revealed no adverse effects up to 400 µg/kg (×500 higher than the expected human dose) and pseudoallergy was not seen as well. In a myocardial ischemia-reperfusion model in rats, the GMP-grade LMW fucoidan labeled with technetium-99m detected P-selectin upregulation in vivo. The present study supports the potential of using 99mTc-fucoidan as an imaging agent to detect activated endothelium in humans.

Non-clinical assessment of safety and gadolinium deposition after cumulative administration of gadobenate dimeglumine (MultiHance®) to neonatal and juvenile rats.

To determine the impact of single and cumulative doses of MultiHance on toxicity, pharmacokinetics, tissue gadolinium presence, behavior and neurological function in juvenile rats. Juvenile male and female rats received either physiological saline or MultiHance at 0.6, 1.25 or 2.5 mmol/kg bodyweight. Animals received either single or six consecutive MultiHance administrations and were sacrificed the day after the last administration or after a 60-day treatment-free period. Animals were assessed for behavior, cognitive function, grip strength, gait, pupillary reflex, and auditory reflex, as well as for physical development, sexual maturation and histopathology. Gadolinium presence in brain, femur, kidneys, liver and skin was determined using inductively coupled plasma-mass spectrometry (ICP-MS). No effects of MultiHance on behavior, cognitive function or any other parameter were noted, even for the highest administered cumulative dose (15 mmol/kg). Gadolinium presence was variable across tissues and decreased during the 60-day treatment-free period. The highest levels were noted in the femur and the lowest levels in the brain. Gadolinium presence in juvenile rat brain following single or repeated MultiHance administrations was minimal and non-impactful.

In vivo tumor targeting and biodistribution evaluation of paramagnetic solid lipid nanoparticles for magnetic resonance imaging.

The current study was performed to evaluate the in vivo efficiency of a new nano-sized contrast agent called paramagnetic Solid Lipid Nanoparticles, pSLNs, having promising relaxivity properties for Magnetic Resonance Imaging application. Good stability and stealth properties toward macrophage uptake have been demonstrated. An in vivo MRI study resulted in an improved signal enhancement in the tumor tissue particularly when folate as targeting ligand was used to decorate the nanoparticles surface. Afterward, the biodistribution of pSLNs in several organs was investigated. The accumulation of pSLNs in kidneys, femoral bones, spleen and brain was quite low while high tropism of pSLNs was found for the liver. In this regard, approaches to improve the rate of the hepatic clearance have been proposed.