EP0772458A1 - Use of chelates as x-ray contrast mediums - Google Patents

Use of chelates as x-ray contrast mediums

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Publication number
EP0772458A1
EP0772458A1 EP95927704A EP95927704A EP0772458A1 EP 0772458 A1 EP0772458 A1 EP 0772458A1 EP 95927704 A EP95927704 A EP 95927704A EP 95927704 A EP95927704 A EP 95927704A EP 0772458 A1 EP0772458 A1 EP 0772458A1
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Prior art keywords
dtpa
use according
chelates
rays
diagnostics
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German (de)
French (fr)
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Werner Krause
Ulrich Speck
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Bayer Pharma AG
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Schering AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations

Definitions

  • the invention relates to the use of water-soluble, metal-containing chelates.
  • the X-ray contrast media currently available for uro / angiography and computer tomography are compounds that are based exclusively on triiodoaromatics. Examples include amidotrizoate (ionic monomer), iohexol, iopamidol, iopromide, iopentol, ioversol (nonionic monomers), ioxaglate (ionic dimer), iotrolan and iodixanol (nonionic dimers).
  • iodine-containing contrast agents are known, but have not yet gained any practical importance, although the need for these compounds is very high.
  • a disadvantage of the iodine-containing contrast agents is that there are always free iodine ions in the formulation, which can lead to complications in the thyroid gland.
  • An overactive thyroid can lead to a hyperthyroid metabolic state if the iodide supply is greatly increased by the injection of a contrast medium containing iodine (iodide).
  • iodide contrast medium containing iodine
  • the dose In order to be able to use lanthanide-containing contrast media in X-ray diagnostics, the dose must be increased by a factor of 10 compared to the dose customary in MR diagnostics, which, however, has the disadvantageous consequence that such contrast media are no longer compatible with the patient.
  • gadolinium- or ytterbium-containing contrast agents can be used using synchrotron radiation, although no information is given about the chosen concentration.
  • the object of the invention is to find a replacement for iodine-containing contrast agents in X-ray diagnostics, these contrast agents also being said to be suitable for humans.
  • water-soluble, metal-containing chelates with the elements of atomic numbers 40-42, 50, 51, 56-78, 80, 82 and 83 which do not contain iodine can then be used as X-ray contrast agents if instead of those in the usual way X-ray equipment or CT equipment used x-ray radiation synchrotron radiation is used.
  • the contrast media are preferably used in the formulation and dosage customary for MR diagnostics.
  • monochromatic X-rays can also be used, almost monochromatic X-rays or X-rays above a defined energy range, ie above the K edge of the metal atom contained in the chelates, are used.
  • the advantages of the new method for synchrotron CT are that, firstly, lower-dose and better-tolerated MR contrast agents can be used instead of iodine-containing contrast agents, and secondly that there are no free iodine ions that can lead to thyroid complications.
  • Another advantage is that with higher-energy radiation, the OK edge of gadolinium (51 keV instead of 33 keV for iodine) can be used. Higher radiation energy means that the ionizing effect is significantly reduced, so that the patient's radiation exposure is less important.
  • the energy of the radiation can be adjusted so that it is closer to the K edge than when using the subtraction method in which recordings are made below and above the K edge of the respective contrast medium conventional X-rays is possible due to the wavelength distribution.
  • This allows a significant increase in contrast to be achieved.
  • This increase in contrast is surprisingly so great that even contrast media with a very high osmolality, relatively low solubility in water, or substances which develop such high viscosities in solution that they are only sufficiently thin in a highly diluted form, can be used.
  • novel contrast effects that were previously inaccessible in x-rays or at least not achievable with compatible doses are achieved.
  • the following substances are particularly suitable as metal-containing contrast agents:
  • Lanthanide complexes of the following chelating agents DTPA, DOTA, HP-D03A, EOB-DTPA, BOPTA and DTPA-polylysine and other high molecular complexing agents or macromolecules containing complexing agents see e.g. EP 0430863.
  • the molecular weight of the high molecular weight compounds is preferably> 10000 D.
  • modified complexes such as that Gd-EOB-DTPA are particularly well suited for liver imaging.
  • contrast media which have heavier elements, such as bismuth, lead or tantalum, also have advantages as X-ray contrast media.
  • contrast agents containing tantalum were discussed in DE-OS 28 31 524, but only for conventional polychromatic X-rays and mostly as water-insoluble tantalum powder. With such contrast media, too, it has been found that using synchrotron radiation offers great advantages with regard to the detection of special structures in the body and their diseases.
  • GD-DTPA is administered intravenously in the formulation of 0.5 mol / l, which is customary for MR diagnostics, and in the dosage of 0.1-0.3 mmol / kg of body weight, which is customary for MR diagnostics.
  • an electron storage ring e.g. DESY in Hamburg, 5.8 GeV storage ring at the University of Tskukuba in Ibaraki, Japan or other institutes
  • blood vessels, organs and tissues could be displayed in a much higher contrast according to their blood content, perfusion and the proportion of extracellular space than was previously possible.
  • the recording device consists of a 2.5 GeV storage ring (260 mA, 5T Wiggler) as a light source, a movable silicone plate as a monochromator, a Gd filter for the 2-energy display and an amplifier as a detector.
  • the images are recorded at intervals of 32 msec, once above the K edge of Gd (51 keV) and once below the K edge. After subtracting the two images, blood vessels are displayed.
  • Gd-DOTA is administered intravenously in the formulation of 0.5 mol / l, which is customary for MR diagnostics, and in the dosage of 0.1, 0.3 mmol / kg, which is customary for MR diagnostics.
  • the admission takes place according to the procedure described for Gd-DTPA.
  • Gd-HP-DO3A is administered intravenously in the formulation of 0.5 mol / l customary for MR diagnostics and in the dosage of 0.1 - 0.3 mmol / kg body weight customary for MR diagnostics.
  • the admission takes place according to the procedure described for Gd-DTPA.
  • up to 1 mmol / kg can also be administered. In this case, a particularly high detection sensitivity for tumors and infarcts is achieved.
  • Gd-EOB-DTPA is administered intravenously in the formulation of 1 mol / l customary for MR diagnostics and in the dosage customary for MR diagnostics of 0.01 to 0.3 mmol / kg body weight.
  • the liver can be visualized using synchrotron radiation, since Gd-EOB-DTPA is absorbed by the hepatocytes.
  • Gd-EOB-DTPA is absorbed by the hepatocytes.
  • the uptake takes place 10 minutes to 1 hour after administration in the procedure described for Gd-DTPA.
  • Er-EOB-DTPA is administered intravenously in the formulation customary for MR diagnostics and in the dosage customary for MR diagnostics of 0.01 to 0.3 mmol / kg body weight.
  • Dy-DTPA-polylysine is administered intravenously in the formulation and dose customary for Gd-DTPA in MR diagnostics (G. Schuhmann-Giampieri, H. Schmitt-Willich, T. Frenzel, WR Press, HJ Weinmann, Invest. Radiol. 26: 969-74, (1991)).
  • This substance can be used to display the intravascular space using synchrotron radiation, since the contrast medium is able to remain within the vascular system over a longer period of time. With rapid admission sequences, the tissue perfusion can also be recorded exactly. There is no example of this in the field of classic X-ray contrast media and using conventional X-rays.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The invention concerns the use of water-soluble, metal-containing chelates as X-ray contrast mediums, with a synchrotron radiation.

Description

Verwendung von Chelaten als Röntgenkontrastmittel Use of chelates as X-ray contrast media
Beschreibung:Description:
Die Erfindung betrifft die Verwendung von wasserlöslichen, metallhaltigen Chelaten.The invention relates to the use of water-soluble, metal-containing chelates.
Die zur Zeit verfügbaren Röntgenkontrastmittel für die Uro-/Angiographie und die Computertomographie sind Verbindungen, die ausschließlich auf der Basis von Trijodaromaten aufgebaut sind. Beispiele hierfür sind Amidotrizoat (ionisches Monomer), Iohexol, Iopamidol, Iopromid, Iopentol, Ioversol (nichtionische Monomere), Ioxaglat (ionisches Dimer), Iotrolan und Iodixanol (nichtionische Dimere).The X-ray contrast media currently available for uro / angiography and computer tomography are compounds that are based exclusively on triiodoaromatics. Examples include amidotrizoate (ionic monomer), iohexol, iopamidol, iopromide, iopentol, ioversol (nonionic monomers), ioxaglate (ionic dimer), iotrolan and iodixanol (nonionic dimers).
Parenterale Röntgenkontrastmittel ohne Jod sind zwar bekannt, haben bisher aber keine praktische Bedeutung erlangt, obwohl das Bedürfnis nach diesen Verbindungen sehr hoch ist. Ein Nachteil der jodhaltigen Kontrastmittel liegt darin, daß in der Formulierung immer freie Jodionen vorkommen, die zu Komplikationen an der Schilddrüse führen können. Eine Überfunktion der Schilddrüse kann dann zu einer hyperthyreoten Stoffwechsellage führen, wenn das Jodidangebot durch die Injektion eines Jod-(Jodid)-haltigen Kontrastmittels stark erhöht wird. Als Folge kann eine thyreotoxische Krise entstehen, die beispielsweise in B. Glöbel, Kontrastmittel in der Praxis, Springer- Verlag, Seite 80 - 82 (1993) beschrieben wird.Parenteral X-ray contrast media without iodine are known, but have not yet gained any practical importance, although the need for these compounds is very high. A disadvantage of the iodine-containing contrast agents is that there are always free iodine ions in the formulation, which can lead to complications in the thyroid gland. An overactive thyroid can lead to a hyperthyroid metabolic state if the iodide supply is greatly increased by the injection of a contrast medium containing iodine (iodide). As a result, a thyreotoxic crisis can arise, which is described, for example, in B. Glöbel, Contrast Agent in Practice, Springer-Verlag, pages 80-82 (1993).
Daneben werden allergieartige Nebenwirkungen häufig mit dem Jodgehalt der gebräuchlichen Röntgenkontrastmittel in Verbindung gebracht. Untersuchungen von C. Zwicker, M. Langer, V. Urich, R. Felix, "Kontrastgebung von Jod, Gadolinium und Ytterbium in CT; in-vitro- und tierexperimentelle Untersuchungen", RöFo 158, 256 - 259 (1993) mit lanthanidenhaltigen Substanzen wie Gd-DTPA haben gezeigt, daß mit diesen Verbindungen keine für die Röntgendiagnostik universell verwendbaren Lösungen herzustellen sind. Daran ist auch die Verwendung der beschriebenen Verbindungen gescheitert.In addition, allergy-like side effects are often associated with the iodine content of the usual X-ray contrast media. Investigations by C. Zwicker, M. Langer, V. Urich, R. Felix, "Contrasting iodine, gadolinium and ytterbium in CT; in-vitro and animal experiments", RöFo 158, 256 - 259 (1993) with lanthanide-containing substances such as Gd-DTPA have shown that these compounds cannot be used to produce solutions that can be used universally for X-ray diagnostics. This also failed the use of the connections described.
Um in der Röntgendiagnostik lanthanidenhaltige Kontrastmittel einsetzen zu können, muß die Dosis gegenüber der in der MR-Diagnostik üblichen Dosis um etwa den Faktor 10 angehoben werden, was allerdings die nachteilige Folge aufweist, daß derartige Kontrastmittel nicht mehr für den Patienten verträglich sind.In order to be able to use lanthanide-containing contrast media in X-ray diagnostics, the dose must be increased by a factor of 10 compared to the dose customary in MR diagnostics, which, however, has the disadvantageous consequence that such contrast media are no longer compatible with the patient.
In H.D. Zeman, DP. Siddons Nucl. Instrum. Methods Physics, Res. Section A, 1990, A 291 (1 - 2), 67 - 73 wird erwähnt, daß gadolinium- oder ytterbiumhaltige Kontrastmittel unter Anwendung von Synchrotronstrahlung eingesetzt werden können, wobei allerdings keine Angaben über die gewählten Konzentration gemacht werden.In H.D. Zeman, DP. Siddons Nucl. Instrument. Methods Physics, Res. Section A, 1990, A 291 (1-2), 67-73 mentions that gadolinium- or ytterbium-containing contrast agents can be used using synchrotron radiation, although no information is given about the chosen concentration.
Aufgabe der Erfindung ist es, einen Ersatz für jodhaltige Kontrastmittel in der Röntgendiagnostik zu finden, wobei diese Kontrastmittel sich auch durch eine entsprechende Verträglichkeit beim Menschen auszeichnen sollen.The object of the invention is to find a replacement for iodine-containing contrast agents in X-ray diagnostics, these contrast agents also being said to be suitable for humans.
Es wurde gefunden, daß wasserlösliche, metallhaltige Chelate mit den Elementen der Ordnungszahlen 40-42, 50, 51, 56-78, 80, 82 und 83, die kein Jod enthalten, dann als Röntgenkontrastmittel verwendet werden können, wenn anstelle der in den üblichen Röntgengeräten oder CT-Apparaten verwendeten Röntgenstrahlung Synchrotronstrahlung eingesetzt wird. Vorzugsweise werden die Kontrastmittel in der für die MR-Diagnostik üblichen Formulierung und Dosierung eingesetzt. Anstelle von Synchrotronstrahlung kann auch monochromatische Röntgenstrahlung, nahezu monochromatische Röntgenstrahlung oder Röntgenstrahlung oberhalb eines definierten Energiebereichs, d.h. oberhalb der K-Kante des jeweils in den Chelaten enthaltenen Metallatoms eingesetzt werden.It has been found that water-soluble, metal-containing chelates with the elements of atomic numbers 40-42, 50, 51, 56-78, 80, 82 and 83 which do not contain iodine can then be used as X-ray contrast agents if instead of those in the usual way X-ray equipment or CT equipment used x-ray radiation synchrotron radiation is used. The contrast media are preferably used in the formulation and dosage customary for MR diagnostics. Instead of synchrotron radiation, monochromatic X-rays can also be used, almost monochromatic X-rays or X-rays above a defined energy range, ie above the K edge of the metal atom contained in the chelates, are used.
Die Vorteile des neuen Verfahrens für die Synchrotron-CT liegen darin, daß erstens niedriger dosierte und besser verträgliche MR-Kontrastmittel anstelle jodhaltiger Kontrastmittel eingesetzt werden können und daß zweitens keine freien Jodionen vorhanden sind, die zu thyreotoxischen Komplikationen führen können.The advantages of the new method for synchrotron CT are that, firstly, lower-dose and better-tolerated MR contrast agents can be used instead of iodine-containing contrast agents, and secondly that there are no free iodine ions that can lead to thyroid complications.
Ein weiterer Vorteil besteht darin, daß bei höherenergetischer Strahlung OK- Kante von Gadolinium: 51 keV anstelle von 33 keV für Jod) gearbeitet werden kann. Höhere Strahlenenergie bedeutet, daß die ionisierende Wirkung deutlich herabgesetzt ist, so daß die Strahlenexposition des Patienten weniger ins Gewicht fallt.Another advantage is that with higher-energy radiation, the OK edge of gadolinium (51 keV instead of 33 keV for iodine) can be used. Higher radiation energy means that the ionizing effect is significantly reduced, so that the patient's radiation exposure is less important.
Dadurch, daß die Synchrotronstrahlung monochromatisch ist, kann bei Anwendung der Subtraktionsmethode, bei der Aufnahmen unterhalb und oberhalb der K-Kante des jeweiligen Kontrastmittels durchgeführt werden, die Energie der Strahlung so eingestellt werden, daß sie dichter an der K-Kante liegt als dies mit herkömmlicher Röntgenstrahlung aufgrund der Wellenlängenverteilung möglich ist. Dadurch kann eine erhebliche Kontraststeigerung erzielt werden. Diese Kontraststeigerung ist überraschenderweise so groß, daß selbst Kontrastmittel mit sehr hoher Osmolalität, verhältnismäßig geringer Wasserlöslichkeit, oder Substanzen, die in Lösung so hohe Viskositäten entwickeln, daß sie nur in stark verdünnter Form hinreichend dünnflüssig sind, eingesetzt werden können. Darüberhinaus werden neuartige, bisher im Röntgen nicht zugängliche oder jedenfalls bei verträglichen Dosierungen nicht erzielbare Kontrasteffekte erreicht. Als metallhaltige Kontrastmittel kommen insbesondere folgende Substanzen infrage:Because the synchrotron radiation is monochromatic, the energy of the radiation can be adjusted so that it is closer to the K edge than when using the subtraction method in which recordings are made below and above the K edge of the respective contrast medium conventional X-rays is possible due to the wavelength distribution. This allows a significant increase in contrast to be achieved. This increase in contrast is surprisingly so great that even contrast media with a very high osmolality, relatively low solubility in water, or substances which develop such high viscosities in solution that they are only sufficiently thin in a highly diluted form, can be used. In addition, novel contrast effects that were previously inaccessible in x-rays or at least not achievable with compatible doses are achieved. The following substances are particularly suitable as metal-containing contrast agents:
Lanthaniden-Komplexe der folgenden Chelatbildner DTPA, DOTA, HP- D03A, EOB-DTPA, BOPTA und DTPA-Polylysin und andere hochmolekulare Komplexbildner oder Komplexbildner enthaltende Makromoleküle (s z.B. EP 0430863).Lanthanide complexes of the following chelating agents DTPA, DOTA, HP-D03A, EOB-DTPA, BOPTA and DTPA-polylysine and other high molecular complexing agents or macromolecules containing complexing agents (see e.g. EP 0430863).
Vorzugsweise beträgt das Molekulargewicht der hochmolekularen Verbindungen > 10000 D.The molecular weight of the high molecular weight compounds is preferably> 10000 D.
Hierbei hat sich herausgestellt, modifizierte Komplexe, wie z.B. daß Gd-EOB- DTPA insbesondere gut geeignet sind für die Darstellung der Leber.It has been found that modified complexes, such as that Gd-EOB-DTPA are particularly well suited for liver imaging.
Weiterhin hat sich gezeigt, daß Kontrastmittel, die schwerere Elemente, wie Wismut, Blei oder Tantal aufweisen, ebenfalls als Röntgenkontrastmittel Vorteile aufweisen. Zwar wurden in der Vergangenheit beispielsweise tantalhaltige Kontrastmittel in der DE-OS 28 31 524 diskutiert, allerdings nur für konventionelle polychromatische Röntgenstrahlung und meist als wasserunlösliches Tantalpulver. Auch bei derartigen Kontrastmitteln hat sich gezeigt, daß unter Anwendung der Synchrotronstrahlung große Vorteile im Hinblick auf den Nachweis spezieller Strukturen im Körper und deren Erkrankungen gefunden werden.Furthermore, it has been shown that contrast media which have heavier elements, such as bismuth, lead or tantalum, also have advantages as X-ray contrast media. In the past, for example, contrast agents containing tantalum were discussed in DE-OS 28 31 524, but only for conventional polychromatic X-rays and mostly as water-insoluble tantalum powder. With such contrast media, too, it has been found that using synchrotron radiation offers great advantages with regard to the detection of special structures in the body and their diseases.
I. Darstellung des ExtrazellulärraumesI. Representation of the extracellular space
1. GD-DTPA1. GD-DTPA
GD-DTPA wird in der für die MR-Diagnostik übliche Formulierung von 0,5 mol/1 und in der für MR-Diagnostik übliche Dosierung von 0,1 - 0,3 mmol/kg Körpergewicht intravenös verabreicht. Mittels Synchrotronstrahlung eines Elektronenspeicherrings (z.B. DESY in Hamburg, 5,8 GeV-Speicherring an der Universität von Tskukuba in Ibaraki, Japan oder anderen Instituten) konnten Blutgefäße, Organe und Gewebe entsprechend ihrem Blutgehalt, der Perfusion und dem Anteil an Extrazellulärraum weitaus kontrastreicher dargestellt werden als dies bisher möglich war.GD-DTPA is administered intravenously in the formulation of 0.5 mol / l, which is customary for MR diagnostics, and in the dosage of 0.1-0.3 mmol / kg of body weight, which is customary for MR diagnostics. By means of synchrotron radiation from an electron storage ring (e.g. DESY in Hamburg, 5.8 GeV storage ring at the University of Tskukuba in Ibaraki, Japan or other institutes), blood vessels, organs and tissues could be displayed in a much higher contrast according to their blood content, perfusion and the proportion of extracellular space than was previously possible.
Das Aufnahmegerät besteht aus einem 2,5 GeV-Speicherring (260 mA, 5T Wiggler) als Lichtquelle, einer beweglichen Silikonplatte als Monochromator, einem Gd-Filter für die 2-Energie-Darstellung und einem Verstärker als Detektor. Die Bilder werden in Intervallen von 32 msec aufgenommen, einmal oberhalb der K-Kante von Gd (51 keV) und einmal unterhalb der K-Kante. Nach Subtraktion der beiden Bilder erhält man die Darstellung von Blutgefäßen.The recording device consists of a 2.5 GeV storage ring (260 mA, 5T Wiggler) as a light source, a movable silicone plate as a monochromator, a Gd filter for the 2-energy display and an amplifier as a detector. The images are recorded at intervals of 32 msec, once above the K edge of Gd (51 keV) and once below the K edge. After subtracting the two images, blood vessels are displayed.
2. Gd-DOTA2. Gd-DOTA
Gd-DOTA wird in der für MR-Diagnostik üblichen Formulierung von 0,5 mol/1 und in der für die MR-Diagnostik üblichen Dosierung von 0,1, - 0,3 mmol/kg intravenös verabreicht. Die Aufnahme erfolgt entsprechend der für Gd-DTPA beschriebenen Verfahrensweise.Gd-DOTA is administered intravenously in the formulation of 0.5 mol / l, which is customary for MR diagnostics, and in the dosage of 0.1, 0.3 mmol / kg, which is customary for MR diagnostics. The admission takes place according to the procedure described for Gd-DTPA.
3. Gd-HP-DO3A3. Gd-HP-DO3A
Gd-HP-DO3A wird in der für die MR-Diagnostik üblichen Formulierung von 0,5 mol/l und in der für die MR-Diagnostik üblichen Dosierung von 0,1 - 0,3 mmol/kg Körpergewicht intravenös verabreicht. Die Aufnahme erfolgt entsprechend der für Gd-DTPA beschriebenen Verfahrensweise. Alternativ können auch bis 1 mmol/kg verabreicht werden. In diesem Falle wird eine besonders hohe Nachweisempfindlichkeit für Tumore und Infarkte erzielt. II. Darstellung der LeberGd-HP-DO3A is administered intravenously in the formulation of 0.5 mol / l customary for MR diagnostics and in the dosage of 0.1 - 0.3 mmol / kg body weight customary for MR diagnostics. The admission takes place according to the procedure described for Gd-DTPA. Alternatively, up to 1 mmol / kg can also be administered. In this case, a particularly high detection sensitivity for tumors and infarcts is achieved. II. Representation of the liver
1. Gd-EOB-DTPA1. Gd-EOB-DTPA
Gd-EOB-DTPA wird in der für die MR-Diagnostik üblichen Formulierung von 1 mol/l und in der für die MR-Diagnostik üblichen Dosierung von 0,01 bis 0,3 mmol/kg Körpergewicht intravenös verabreicht.Gd-EOB-DTPA is administered intravenously in the formulation of 1 mol / l customary for MR diagnostics and in the dosage customary for MR diagnostics of 0.01 to 0.3 mmol / kg body weight.
Mit dieser Substanz ist unter Verwendung von Synchrotronstrahlung die Darstellung der Leber möglich, da Gd-EOB-DTPA von den Hepatozyten aufgenommen wird. Hierfür gibt es im Bereich der klassischen wasserlöslichen Röntgenkontrastmittel und unter Verwendung von konventioneller Röntgenstrahlung kein Beispiel, bei dem ausreichende Kontrastmittelkonzentrationen in der Leber erreicht werden.With this substance, the liver can be visualized using synchrotron radiation, since Gd-EOB-DTPA is absorbed by the hepatocytes. There is no example of this in the area of classic water-soluble X-ray contrast media and using conventional X-ray radiation, in which sufficient contrast agent concentrations are achieved in the liver.
Die Aufnahme erfolgt 10 min bis 1 h nach Verabreichung in der für Gd-DTPA beschriebenen Verfahrensweise. Anstelle der Zwei- Wellenlängenaufnahmen kann hier auch bei nur einer Energie (>52 keV) gearbeitet werden.The uptake takes place 10 minutes to 1 hour after administration in the procedure described for Gd-DTPA. Instead of the two-wavelength recordings, it is also possible to work with only one energy (> 52 keV).
2. Er-EOB-DTPA2. He-EOB-DTPA
Er-EOB-DTPA wird in der für die MR-Diagnostik üblichen Formulierung und in der für die MR-Diagnostik üblichen Dosierung von 0,01 bis 0,3 mmol/kg Körpergewicht intravenös verabreicht.Er-EOB-DTPA is administered intravenously in the formulation customary for MR diagnostics and in the dosage customary for MR diagnostics of 0.01 to 0.3 mmol / kg body weight.
Die Aufnahme erfolgt 30 min bis 1 h nach Verabreichung in der für Gd-DTPA beschriebenen Verfahrensweise. Anstelle der Zwei- Wellenlängenaufnahme kann hier auch bei nur einer Energie (> 52 keV) gearbeitet werden. III. Darstellung des IntravasalraumesThe uptake takes place 30 minutes to 1 hour after administration in the procedure described for Gd-DTPA. Instead of two-wavelength recording, it is also possible to work with only one energy (> 52 keV). III. Representation of the intravascular space
1. Dy-DTPA-Polylysin1. Dy-DTPA polylysine
Dy-DTPA-Polylysin wird in der für Gd-DTPA in der MR-Diagnostik üblichen Formulierung und Dosis intravenös verabreicht (G. Schuhmann-Giampieri, H. Schmitt-Willich, T. Frenzel, W.R. Press, H.J. Weinmann, Invest. Radiol. 26: 969-74, (1991)).Dy-DTPA-polylysine is administered intravenously in the formulation and dose customary for Gd-DTPA in MR diagnostics (G. Schuhmann-Giampieri, H. Schmitt-Willich, T. Frenzel, WR Press, HJ Weinmann, Invest. Radiol. 26: 969-74, (1991)).
Mit dieser Substanz ist unter Verwendung von Synchrotronstrahlung die Darstellung des Intravasalraumes möglich, da das Kontrastmittel in der Lage ist, über einen längeren Zeitraum innerhalb des Gefaßsystems zu verweilen. Mit schnellen Aufnahmefolgen kann darüberhinaus die Gewebedurchblutung exakt erfaßt werden. Hierfür gibt es im Bereich der klassischen Röntgenkontrastmittel und unter Verwendung von konventioneller Röntgenstrahlung kein Beispiel.This substance can be used to display the intravascular space using synchrotron radiation, since the contrast medium is able to remain within the vascular system over a longer period of time. With rapid admission sequences, the tissue perfusion can also be recorded exactly. There is no example of this in the field of classic X-ray contrast media and using conventional X-rays.
Die Aufnahme erfolgt in der für Gd-DTPA beschriebenen Verfahrensweise. The admission takes place in the procedure described for Gd-DTPA.

Claims

Patentansprüche: Claims:
1. Verwendung von wasserlöslichen, metallhaltigen Chelaten mit den1. Use of water-soluble, metal-containing chelates with the
Elementen der Ordnungszahlen 40-42, 50, 51, 56-78, 80, 82 und 83 als Röntgenkontrastmittel bei Anwendung von Synchrotronstrahlung.Elements of atomic numbers 40-42, 50, 51, 56-78, 80, 82 and 83 as X-ray contrast agents when using synchrotron radiation.
2. Verwendung nach Anspruch 1 in der für die MR-Diagnostik üblichen Formulierung und Dosierung.2. Use according to claim 1 in the formulation and dosage customary for MR diagnostics.
3. Verwendung nach einem der Anspsüche 1 oder 2, wobei anstelle der Synchrotronstrahlung monochromatische Röntgenstrahlung, nahezu monochromatische Röntgenstrahlung oder Röntgenstrahlung oberhalb eines definierten Energiebereiches angewendet wird.3. Use according to one of claims 1 or 2, wherein monochromatic X-rays, almost monochromatic X-rays or X-rays above a defined energy range are used instead of synchrotron radiation.
4. Verwendung nach einem der Ansprüche 1 bis 3, wobei die metallhaltigen Kontrastmittel Gd-DTPA, Gd-DOTA, Gd-HP-DO3A, Gd-EOB-DTPA, Gd-BOPTA, Gd-DTPA-BMA, Dy-DTPA-BMA, Gd- DTPA-Polylysin, Gd-DTPA-Kaskadenpolymere enthalten.4. Use according to one of claims 1 to 3, wherein the metal-containing contrast agents Gd-DTPA, Gd-DOTA, Gd-HP-DO3A, Gd-EOB-DTPA, Gd-BOPTA, Gd-DTPA-BMA, Dy-DTPA-BMA , Gd-DTPA polylysine, Gd-DTPA cascade polymers contain.
5. Verwendung von Chelaten nach einem der Ansprüche 1 bis 4, wobei das Molekulargewicht der hochmolekularen Verbindungen5. Use of chelates according to one of claims 1 to 4, wherein the molecular weight of the high molecular weight compounds
> 10000 D beträgt.Is> 10000 D.
6. Verwendung nach einem der Ansprüche 1 bis 5 zur Darstellung des Extrazellulärraumes.6. Use according to one of claims 1 to 5 for representing the extracellular space.
7. Verwendung nach einem der Ansprüche 1 bis 5 zur Darstellung der Leber.7. Use according to one of claims 1 to 5 for the representation of the liver.
8. Verwendung nach einem der Ansprüche 1 bis 5 zur Darstellung des Intravasalraumes. 8. Use according to one of claims 1 to 5 to illustrate the intravascular space.
9. Verwendung nach einem der Ansprüche 1 bis 5 zur Darstellung von gesundem und pathologisch verändertem Gewebe. 9. Use according to one of claims 1 to 5 for the representation of healthy and pathologically modified tissue.
EP95927704A 1994-07-26 1995-07-21 Use of chelates as x-ray contrast mediums Withdrawn EP0772458A1 (en)

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DE4426438A DE4426438A1 (en) 1994-07-26 1994-07-26 Use of chelates as X-ray contrast media
DE4426438 1994-07-26
PCT/EP1995/002901 WO1996003154A1 (en) 1994-07-26 1995-07-21 Use of chelates as x-ray contrast mediums

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WO1996024381A2 (en) * 1995-02-09 1996-08-15 Schering Aktiengesellschaft Liposomes containing contrast media for blood pool imaging
EP1136082A1 (en) * 2000-03-24 2001-09-26 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Local drug delivery
DE10118792B4 (en) * 2001-04-05 2005-12-22 Schering Ag Arrangement for recording projection mammograms and using the arrangement for projection mammography
US8501223B2 (en) 2003-06-20 2013-08-06 Hill's Pet Nutrition, Inc. Methods for dietary management of cats to avoid hyperthyroidism
ES2359818T3 (en) * 2003-06-20 2011-05-27 Hill's Pet Nutrition, Inc. METHODS FOR HYPERTIROIDISM IN A CAT AND COMPOSITION THAT INCLUDES LIMITED IODINE.
US9132207B2 (en) 2009-10-27 2015-09-15 Spine Wave, Inc. Radiopaque injectable nucleus hydrogel compositions

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US4432370A (en) * 1981-10-14 1984-02-21 The Board Of Trustees Of The Leland Stanford Junior University Method and means for minimally invasive angiography using mono-chromatized synchrotron radiation
US4478816A (en) * 1982-06-07 1984-10-23 Georgetown University Rare earth/chelating agent complex for digital fluoroscopy
DE3938992A1 (en) * 1989-11-21 1991-05-23 Schering Ag Cascade polymer-bound complex formers, their complexes and conjugates, process for their preparation and pharmaceutical compositions containing them
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IL114710A0 (en) 1995-11-27
AU3164395A (en) 1996-02-22

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