Method for enhancing the safety of metal-ligand chelates as magnetic resonance imaging agents by addition of calcium ions

Paramagnetic chelates, as for example, Gadolinium diethylenetriaminepentaacetic acid (DTPA), manganese, ethylenediaminetetraacetic acid (EDTA), and others used as magnetic resonance imaging contrast agents are more toxic acutely when injected in high concentration or at rapid rates. The use of effective amounts of calcium in the form of, calcium chloride, calcium gluconate, or balanced salt solutions substantially reduces this toxicity without the need to add additional ligand.

EXAMPLE 1 
The intravenous LD.sub.50 for calcium chloride (CaCl.sub.2) in the mouse is 
reported to be 42 mg/kg (RTECS). This calculates to about 15 mg/kg of 
calcium or about 0.3 mg of calcium for a 20 gram mouse. When calcium 
chloride was added to 0.68M disodium gadolinium 
diethyenetriaminepentaacetic acid (Na.sub.2 GdDTPA) at 130 mg/kg (6.5 
mg/ml) or 260 mg/kg (13.0 mg/ml) the lethal effects of the Na.sub.2 GdDTPA 
were greatly diminished even though these levels of added calcium would 
provide 47 and 94 mg/kg, i.e. 0.94 and 1.88 mg respectively to a 20 gram 
mouse. These values are 3.1 and 6.2 times higher than the i.v. LD.sub.50 
of calcium administered as CaCl.sub.2. Whereas 4 of 4 mice given 13.6 
mMol/kg of Na.sub.2 GdDTPA alone died, only 1 of 4 mice died at those 
doses of Na.sub.2 GdDTPA with 2.34 mg/ml of added calcium and 2 of 4 died 
at the 4.68 mg/ml level of added calcium. Clearly then the 0.68 m Na.sub.2 
GdDTPA solution must complex a substantial amount of the added calcium in 
a way to block the calcium's in-vivo toxicity. 
Conversely, the calcium added to the Na.sub.2 GdDTPA formulation blocks the 
in vivo calcium complexation by Na.sub.2 GdDTPA and thereby reduces its 
toxicity, i.e. prevents tetanic convulsions and death. Clearly this 
protective effect of added calcium must be balanced to the calcium 
complexing potential of the paramagnetic contrast agent. 
EXAMPLE 2 
Addition of calcium chloride at 430 (21.5 mg/ml and 860 mg/kg (43 mg/ml), 
i.e. at 155 and 310 mg of calcium /kg, results in doses of 3.1 and 6.2 mg 
of calcium per 20 gram mouse. These doses of calcium added to 0.68 m 
Na.sub.2 GdDTPA were not protective and did not enhance the safety of the 
Na.sub.2 GdDTPA formulation. All mice injected with 0.65 m NAGdDTPA at 
those two dose levels of calcium died. It may be inferred that these 
levels of added calcium were excessive and exceeded the calcium binding 
optimum of the solution and that death from calcium toxicity ensued. 
In these examples 1 and 2 (see Table 1) it is shown that calcium added to 
0.68 m Na.sub.2 GdDTPA as calcium chloride at concentrations of 6.5, 13.0, 
21.5 and 43 mg/ml of solution and which would result in concentrations of 
calcium of 2.34 mg, 4.68 mg, 7.74 mg and 15.48 mg per milliliter 
respectively, provided different levels of protection against the toxicity 
of Na.sub.2 GdDTPA. On a stoichiometric basis the four added calcium 
levels approximate 9%, 17%, 29% and 57% respectively of the 0.68 m 
concentration of Na.sub.2 GdDTPA. Based on this data, concentrations of 
added calcium of 30-60% stoichiometric to that of the subject formulation 
are excessive and do not enhance the safety. However, concentrations of 
added calcium of 9-17% stoichiometry to the subject formulation were 
protective based on acute toxicity determinations. 
Clearly the optimum amount of calcium to be added will vary based on the 
ligand chosen and its concentration in the forumulation. 
TABLE 1 
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STUDIES ON INTRAVENOUS TOXICITY OF Na.sub.2 GdDTPA ALONE 
AND ADDED CaCL.sub.2 
Mice Calcium, % 
Dose of Added No. No. Approximate 
Stoichiometry to 
Na.sub.2 GdDTPA 
Calcium mg/ml 
Deaths/Injected 
LD Values 
Na.sub.2 GdDTPA 
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13.6 mMol/kg 
0 4/4 100% 0 
13.6 mMol/kg 
2.34 1/4 25% 9% 
13.6 mMol/kg 
4.68 2/4 50% 17% 
13.6 mMol/kg 
7.74 4/4 100% 29% 
13.6 mMol/kg 
15.48 2/2 100% 57% 
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