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WO1996003154A1 - Utilisation de chelates en tant qu'agents de contraste pour rayons x - Google Patents

Utilisation de chelates en tant qu'agents de contraste pour rayons x Download PDF

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Publication number
WO1996003154A1
WO1996003154A1 PCT/EP1995/002901 EP9502901W WO9603154A1 WO 1996003154 A1 WO1996003154 A1 WO 1996003154A1 EP 9502901 W EP9502901 W EP 9502901W WO 9603154 A1 WO9603154 A1 WO 9603154A1
Authority
WO
WIPO (PCT)
Prior art keywords
dtpa
use according
chelates
rays
diagnostics
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1995/002901
Other languages
German (de)
English (en)
Inventor
Werner Krause
Ulrich Speck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to AU31643/95A priority Critical patent/AU3164395A/en
Priority to JP8505459A priority patent/JPH10502935A/ja
Priority to EP95927704A priority patent/EP0772458A1/fr
Publication of WO1996003154A1 publication Critical patent/WO1996003154A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

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

Abstract

L'invention concerne l'utilisation de chélates métalliques hydrosolubles, en tant qu'agents de contraste pour rayons X, avec un rayonnement synchrotron.
PCT/EP1995/002901 1994-07-26 1995-07-21 Utilisation de chelates en tant qu'agents de contraste pour rayons x Ceased WO1996003154A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU31643/95A AU3164395A (en) 1994-07-26 1995-07-21 Use of chelates as x-ray contrast mediums
JP8505459A JPH10502935A (ja) 1994-07-26 1995-07-21 Ｘ線造影剤としてのキレートの使用
EP95927704A EP0772458A1 (fr) 1994-07-26 1995-07-21 Utilisation de chelates en tant qu'agents de contraste pour rayons x

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4426438A DE4426438A1 (de) 1994-07-26 1994-07-26 Verwendung von Chelaten als Röntgenkontrastmittel
DEP4426438.0 1994-07-26

Publications (1)

Publication Number Publication Date
WO1996003154A1 true WO1996003154A1 (fr) 1996-02-08

Family

ID=6524171

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/002901 Ceased WO1996003154A1 (fr) 1994-07-26 1995-07-21 Utilisation de chelates en tant qu'agents de contraste pour rayons x

Country Status (7)

Country Link
EP (1) EP0772458A1 (fr)
JP (1) JPH10502935A (fr)
AU (1) AU3164395A (fr)
DE (1) DE4426438A1 (fr)
IL (1) IL114710A0 (fr)
WO (1) WO1996003154A1 (fr)
ZA (1) ZA956227B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501223B2 (en) 2003-06-20 2013-08-06 Hill's Pet Nutrition, Inc. Methods for dietary management of cats to avoid hyperthyroidism

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0806969A2 (fr) * 1995-02-09 1997-11-19 Schering Aktiengesellschaft Liposomes contenant des agents de contraste pour l'imagerie relative au pool sanguin intracardiaque
EP1136082A1 (fr) * 2000-03-24 2001-09-26 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Administration locale de médicaments
DE10118792B4 (de) * 2001-04-05 2005-12-22 Schering Ag Anordnung zur Aufnahme von Projektionsmammogrammen und Verwendung der Anordnung für die Projektionsmammographie
AU2004249301B2 (en) * 2003-06-20 2011-01-20 Hill's Pet Nutrition, Inc. Methods for hyperthyroidism in a cat and composition comprising limited iodine
US9132207B2 (en) * 2009-10-27 2015-09-15 Spine Wave, Inc. Radiopaque injectable nucleus hydrogel compositions

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0430863A2 (fr) * 1989-11-21 1991-06-05 Schering Aktiengesellschaft Formateur de complexe lié à un polymère préparé par étapes, ses complexes et conjugats, procédé de préparation et substances pharmaceutiques les contenant
WO1993016375A1 (fr) * 1992-02-06 1993-08-19 Mallinckrodt Medical, Inc. Agents de contraste utilises pour les radiographies et l'irm

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0430863A2 (fr) * 1989-11-21 1991-06-05 Schering Aktiengesellschaft Formateur de complexe lié à un polymère préparé par étapes, ses complexes et conjugats, procédé de préparation et substances pharmaceutiques les contenant
WO1993016375A1 (fr) * 1992-02-06 1993-08-19 Mallinckrodt Medical, Inc. Agents de contraste utilises pour les radiographies et l'irm

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 113, no. 9, 27 August 1990, Columbus, Ohio, US; abstract no. 73900, ZEMAN, H. D. ET AL: "Contrast agent choice for intravenous coronary angiography" *
DATABASE BIOSIS BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; *
DATABASE EMBASE ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; *
DIX W.R.: "INTRAVENOUS CORONARY ANGIOGRAPHY WITH SYNCHRTRON RADIATION.", PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY, vol. 63, no. 2, pages 159 - 191 *
NUCL. INSTRUM. METHODS PHYS. RES., SECT. A (1990), A291(1-2), 67-73 CODEN: NIMAER;ISSN: 0168-9002 *
O' HARE N.J.: "CONTRAST AGENT CT IMAGING IN VARIABLE SIZED ORGANS USING SINGLE ENERGY SYNCHROTRON RADIATION.", PHYS. MED. BIOL., vol. 37, no. 7, pages 1519 - 1530, XP000280557, DOI: doi:10.1088/0031-9155/37/7/004 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501223B2 (en) 2003-06-20 2013-08-06 Hill's Pet Nutrition, Inc. Methods for dietary management of cats to avoid hyperthyroidism

Also Published As

Publication number Publication date
JPH10502935A (ja) 1998-03-17
AU3164395A (en) 1996-02-22
DE4426438A1 (de) 1996-02-01
IL114710A0 (en) 1995-11-27
ZA956227B (en) 1996-03-14
EP0772458A1 (fr) 1997-05-14

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