Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1996-10-03
1998-06-02
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 165, 424 942, 424 9364, 424 9365, 534 10, 534 14, 534 15, 534 16, A61B 5055, A61K 5104, A61K 4904, C07F 500
Patent
active
057595186
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the object characterized in the claims, i.e., new metal complexes of dendrimeric macromolecules, agents that contain these compounds, the use of the complexes in diagnosis as well as processes for the production of these complexes and agents.
Magnevist.RTM. (Gd-I)TPA/dimeglumine) is the first registered contrast medium for nuclear spin tomography (MRI=magnetic resonance imaging). It is especially well-suited for the diagnosis of pathological areas (e.g., inflammations, tumors, etc.). After intravenous injection, the compound is eliminated. through the kidneys; an extrarenal excretion is practically not observed.
A drawback of Magnevist.RTM. is that after intravenous administration, it is dispersed uniformly between the vascular space and the interstitial space. Thus, a delimitation of the vessels relative to the surrounding interstitial space is not possible.
For perfusion studies, a contrast medium is necessary, which is dispersed exclusively in the vascular space. Such a "blood-pool agent" makes it possible to delimit tissue that is well supplied with blood from tissue with insufficient blood supply with the aid of nuclear spin tomography and thus to diagnose an ischemia.
Other applications are vasography with the aid of nuclear spin tomography (so-called MR-angiography) and the graphic visualization of permeability disorders of blood vessels (such as, e.g., in malignant tumors).
So far, most patients in whom suspicion of a cardiovascular disease exists (this disease is the most -frequent cause of death in Western industrialized countries) have to undergo invasive diagnostic studies. In angiography, at present primarily diagnostic radiology with the aid of iodine-containing contrast media is used. These studies are associated with various drawbacks:
They are associated with the risk of radiation exposure as well as with difficulties and stresses, which are caused primarily by the fact that the iodine-containing contrast media, compared with NMR contrast media, have to be used at much higher concentration and do not remain in the vascular space.
There therefore exists a need for NMR contrast media, which can label the vascular space (blood-pool agent). These compounds are to be distinguished by good compatibility and by high effectiveness (high increase of the signal intensity with MRI).
The attempt to solve at least a part of these problems by using complexing agents, which are bound to macromolecules or biomolecules, has thus far been successful only to a very limited extent.
Thus, for example, the number of paramagnetic centers in the complexes, which are described in European Patent Applications 0 088 695 and 0 150 884, are not sufficient for satisfactory imaging.
Macromolecules are generally suitable as contrast media for angiography. 24 hours after intravenous injection in rats, however, albumin-Gd-DTPA (Radiology 1987; 162:205), e.g., shows a concentration in liver tissue, which constitutes almost 30% of the dose. Furthermore, only 20% of the dose is eliminated within 24 hours.
In EP 0 233 619, blood-pool agents based on polylysine-Gd-DTPA are described. These compounds are associated with the drawback, however, that only an unsatisfactory excretion of the complexes and thus of the heavy metal ions that are contained in the complexes is carried out.
The cascade polymer complexes that are described in EP 0 430 863 provided an improvement relative to the capability of excretion. Here, too, however, a complete excretion does not take place within a reasonable period, so that the danger of release of the metal from the complex exists.
Macromolecular contrast media that are based on carbohydrates, e.g., dextran, have also been described (European Patent Application 0 326 226). The drawback of these compounds lies in the fact that they generally carry only 4.6% of the signal-amplifying paramagnetic cation.
The object of this invention was therefore to find new diagnostic agents primarily to detect vascular diseases that do not have the above-mentioned drawbacks, i.e., to find met
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Frenzel Thomas
Muhler Andreas
Platzek Johannes
Schmitt-Willich Heribert
Hartley Michael G.
Hollinden Gary E.
Schering Aktiengesellschaft
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