Introduction Gadolinium-based contrast agents (GBCA) have been used to enhance magnetic resonance imaging (MRI) since 1985. Recently, the media and online groups have voiced concerns about gadolinium deposition in patients with normal renal function based on Belevated^urinary gadolinium levels. The determination of increased urinary gadolinium levels is based on reference ranges developed in individuals with normal renal function who were never exposed to GBCA. Studies suggest an elevated gadolinium urinary elimination greater than 72 h post GBCA scan. We evaluated urine gadolinium concentrations over a 30-day period in patients administered GBCA. Methods In this prospective, observational pilot study, we enrolled subjects between 18 and 65 years of age with normal renal function who received GBCA for the first time. Urinary gadolinium was measured at days zero (prior to GBCA exposure), 3, 10, and 30 after GBCA exposure. We compared urinary gadolinium levels after GBCA exposure to the current reference range and calculated an estimated duration of Belevated^gadolinium urine levels in the average patient. Results All 13 subjects had 24-h urinary gadolinium levels higher than 0.7 μg/24 h with means of 1944 (± 1432) μg/24 h on day 3, 301 (± 218) μg/24 h on day 10, and 34 (± 33) μg/24 h on day 30. Based on calculated urinary gadolinium elimination kinetics, we estimate urinary gadolinium levels will often remain above the current reference range for > 50 days. Conclusion The current reference range of 0.7 μg/24 h for 24 h urinary gadolinium is not applicable to patients for at least 30 days following GBCA exposure.

Article: Schiele F, van Ryn J, Newsome C, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121: 3554-3562.Keywords: Dabigatran, Fab antidote, Preclinical research. Background: Advances in anticoagulation for patients at risk for thromboembolic disorders have led from the use of indirect thrombin inhibitors (like warfarin) to direct inhibitors including dabigatran. Dabigatran therapy is more convenient for patients and has less reported complications than warfarin in large studies. However, when bleeding occurs during dabigatran therapy or a need for emergent surgery arises, there is no effective reversal modality and mortality in these circumstances is seemingly high.Research objective: Characterize the structure and test the ability of a novel anti-dabigatran fab to reverse anticoagulant effects x and in vivo.Methods: Antibodies were cloned after dabigatran exposure in mice, purified, and then humanized. The antidabigatran fab was then tested in vitro for the ability to reverse dabigatran anticoagulation, structurally characterized via crystallography, and examined for intrinsic coagulant effect. The derived fab was also tested in vivo in dabigatrananticoagulated rats.Results: Intact mouse antibodies, purified mouse antibodies, and humanized fab bound dabigatran as measured via ELISA. These antibodies also reversed prolonged plasma thrombin time in a dose dependent manner. Detailed crystallography revealed that the final humanized fab is composed of two variable light and heavy chain domains and two constant domains. The dabigatran binding site is a polar pocket surrounded by a hydrophobic area. Dabigatran binds at the polar pocket in a similar manner to thrombin binding. In the third phase of the study, investigators performed further assays to investigate fab binding to thrombin and other thrombin substrates. There was no observed binding nor procoagulant effects. Lastly, a single fab dose reversed prolonged thrombin time in rats despite continuous infusion of dabigatran.Conclusion: The derived anti-dabigatran fab bound with high affinity, reversed anti-coagulant effects in vitro/in vivo, and lacked intrinsic thrombin-like procoagulant effects.Critique: This is an elegant study that demonstrates the ability to produce a novel fab that specifically binds to dabigatran and reverses its anticoagulant effect without untoward procoagulant activity. All investigators are employees of the manufacturer of dabigatran.Implication for toxicologists: This report is promising in that we may have an effective and safe therapy for direct thrombin inhibitor in the reasonable future.Article: Manini AF, Stimmel B, Vlahov D. Racial susceptibility for QT prolongation in acute drug overdose. J Electrocardiol. 2014 (in press).

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