Michael R. Hynes

Measurement of Serum Calcium Concentration After Administration of Four Gadolinium-Based Contrast Agents to Human Volunteers

OBJECTIVE The purpose of this study was to use three analytic methods to measure serum calcium concentration to assess the magnitude and time course of the effects of four gadolinium-based contrast agents. SUBJECTS AND METHODS After providing informed consent, 12 healthy adult volunteers (mean age, 38.6 +/- 13.6 [SD] years) received i.v. injections of gadoversetamide, gadodiamide, gadopentetate dimeglumine, and gadoteridol at a dose of 0.1 mmol/kg. Blood samples were obtained before contrast administration and 5, 10, 15, 30, 60, 90, 120, 180, and 240 minutes after contrast injection. Serum calcium levels were measured with an orthocresolphthalein complexone method, an arsenazo III method, and inductively coupled plasma mass spectrometry (ICP-MS). Analyses of variance coupled with a Dunnett test were used to compare baseline serum calcium measurements with values at the different time points after injection. RESULTS Administration of gadoversetamide or gadodiamide caused no significant change in serum calcium concentration measured with the arsenazo III and ICP-MS analytic methods. However, the orthocresolphthalein assay showed a transient decrease in serum calcium concentration after injection of gadoversetamide or gadodiamide. Injection of gadopentetate or gadoteridol produced no significant change in serum calcium values measured with the orthocresolphthalein, arsenazo III, and ICP-MS methods. CONCLUSION Administration of gadoversetamide or gadodiamide caused no significant effect on serum calcium concentration. Neither gadoversetamide nor gadodiamide interfered with measurement of serum calcium with the arsenazo III or ICP-MS method. However, the orthocresolphthalein method of measuring serum calcium produced a transient hypocalcemia artifact in the presence of gadoversetamide or gadodiamide.

Safety assessment of gadoversetamide (OptiMARK) administered by power injector.

To evaluate the safety of OptiMARK® (gadoversetamide injection) administered via power injector.

Development of a novel nonaromatic small-molecule MR contrast agent for the blood pool

The ideal contrast agent for MR angiography should be safe, efficacious, blood-persistent, and easily excreted. The binding of small Gd chelates to macromolecules has been shown to provide a mechanism of proton relaxation enhancement in MR images through longer rotational correlation times of the macromolecule-bound Gd-chelate complexes (1,2). Several effective macromolecules bearing such covalently attached Gd chelates have been synthesized and evaluated previously for MRA applications. These, however, either proved unsafe (protein precipitants) or had undesirably long blood retention, ie, were not easily excreted (3-6). Reversible noncovalent binding of small Gd chelates to serum albumin (via hydrophobic interactions) produces an efficacious, blood persistent alternative to macromoleculebased MR blood-pool agents without attendant clearance problems (7,8). A prime requirement for this approach is the presence of a lipophilic component on the Gd chelate that can undergo reversible protein binding. An MR blood-pool agent, MS-325, which takes advantage of the binding of aromatic side chains on a Gd-chelate compound to albumin, is under development (2,7,8). We now report the results of our attempt to develop a nonaromatic small Gd 3+ chelate as a contrast agent for MR angiography (ie, MP-2269, a water-soluble MR agent that binds blood proteins reversibly to yield an efficacious blood-pool agent).