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
  • A61K49/04—X-ray contrast preparations
  • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent

Definitions

• the invention relates to the object characterized in the claims.
• contrast media that are not very suitable for this purpose. They are the same compounds used for uro / angiography and computed tomography. Examples of this are Amidotrizoaf » Iohexol *. Iopamidol *. Iopromide *, iopentol *. Ioversol *, Ioxaglaf » Iotrolan * and Iodixanol 9 . Tumors and metastases can only be visualized with these contrast media if they are either hyper- or hypovascularized. Lesions with the same vascular density as healthy tissue are not recognizable.
• Water-soluble X-ray contrast media for the imaging of the liver are not known, although the need for these compounds is very high. In addition, it could be shown (W. Mützel, OH Wegener, R. Souchon, H.-J. Weinmann, in: Amiel M. (ed), Springer-Verlag, Berlin, 1982, pp. 320-3) that so far it was not possible to use water-soluble contrast agents in conventional X-ray diagnostics of the liver to be used because the saturation processes of the transport prevent a sufficiently high concentration in the liver.
• bile contrast agents in the liver are saturable processes that competes with many other substances.
• concentrations reached in the liver are therefore not sufficiently high for imaging in computer tomography (VG Urich, U. Speck: Biliary exeretion of contrast media. Progress in Pharmacology and Clinical Pha ⁇ nacology 8: 167-177 (1991); T. Fritzsch , W. Krause, HJ. Weinmann: Status of contrast media research in MRI, ultrasound and X-ray. Eur. Radiol. 2: 2-13 (1992)).
• contrast media which are well tolerated, which are easy to handle pharmaceutically and are easy to use on the patient, i.e. no major interventions such as require direct application into the hepatic arteries to display the liver using a method which allows a sensitive measurement despite the lowest possible concentration of contrast medium.
• a compound with at least one halogenated aromatic is used as a contrast medium for imaging the liver using synchrotron radiation, approximately monochromatic X-rays or X-rays below a certain wavelength.
• compounds with at least one iodinated aromatic compound are preferably used.
• compounds with at least one triiodinated aromatic are used.
• synchrotron radiation which is monochromatic X-ray radiation
• Radiation above a certain energy means radiation above the K-edge of iodine (33keV).
• the invention is only described on the basis of synchrotron radiation.
• the synchrotron radiation used in accordance with the invention can be, for example, high-energy monochromatic synchrotron radiation (2.5 GeV storage ring, 280 mA, 5 T Wiggler), as is e.g. at the electron synchrotron at the University of Tsukuba in Ibaraki / Japan.
• the synchrotron radiation is in no way limited to the example described.
• this procedure involves taking two x-rays of the liver, one without a filter and the other with a filter. After subtraction processes with an iodine filter (corresponding to the X-rays below the K-edge) and without an iodine filter (X-rays above the K-edge), an image of the ber is obtained.
• the images can be taken at intervals of 32 msec, for example, so that the entire liver can be displayed in one pass without movement artifacts occurring.
• the compounds used according to the invention as a contrast medium to represent the liver have the following structural features:
• the molecular weight of the compound should be in the range of 300 to 1000 regardless of the halogen atom (s).
• the lower limit is determined by the molecular weight that is at least necessary for hepatobiliary excretion. Furthermore, the transport mechanisms of the liver or bile also play a role for the molecular weight limits.
• the compound should have at least one functional group with at least one negative charge, which is bound aromatically or aliphatically.
• a preferred functional group with a negative charge is the carboxyl group. It is a carrier of a negative charge because the COOH group dissociates into COO ' and H + in aqueous medium.
• the compound in addition to the functional group (s), each with at least one negative charge, which increases the anion transport for transfer to the liver / bile, the compound should also have lipophilic regions in the molecule which enable sufficiently high protein binding.
• Structural features that increase lipophilicity are those atoms / groups in a molecule that do not contain oxygen or nitrogen, e.g. pure hydrocarbon residues or the iodine atom itself.
• the hydrophilic and lipophilic areas in the compound used according to the invention should be selected such that the compound in the n-butanol / water system has a distribution coefficient P> 0.2.
• the determination of the Distribution coefficients P are described, for example, by W. Mützel, WR. Press, H.-J. Weinmann: Physicochemical Properties and General Pha ⁇ nacology of the Nonionic Iotrolan, described in advances in the field of X-rays and nuclear medicine, Frommhold W. and Thurn P. (Ed.), Georg Thieme Verlag Stuttgart, 1989, pp. 28-32.
• Biligrafin * (formula I) is administered intravenously in the formulation customary for cholegraphy (representation of the bile).
• the area of the liver is scanned using synchrotron radiation.
• the density of the healthy liver parenchyma is now also increased. Metastases are largely left out. Other lesions (hemangiomas, areas with cirrhotic changes) show typical changes in density over time after the injection. This is not the case with conventional X-rays.
• Biliscopin * (Formula II) is slowly infused in a dose of only 2g iodine.
• Metastases, abscesses, necroses and cysts show practically no change in density over the entire course of time, while the healthy liver parenchyma increases very rapidly, adenomas, focal nodular hyperplasias and fatty cirrhotic areas of the liver slowly increase in density.
• Biloptin * (formula HI) is administered orally in the formulation customary for cholegraphy.
• the area of the liver is scanned using synchrotron radiation.
• the liver parenchyma can now be displayed. This is not the case with conventional X-rays.

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• Health & Medical Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• General Health & Medical Sciences (AREA)
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• Veterinary Medicine (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Apparatus For Radiation Diagnosis (AREA)
• Radiation-Therapy Devices (AREA)

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• 1994
  • 1994-07-26 DE DE4426439A patent/DE4426439C1/de not_active Expired - Fee Related
• 1995
  • 1995-07-21 EP EP95926971A patent/EP0773798A1/de not_active Withdrawn
  • 1995-07-21 JP JP8505460A patent/JPH10502936A/ja not_active Ceased
  • 1995-07-21 AU AU31163/95A patent/AU3116395A/en not_active Abandoned
  • 1995-07-21 WO PCT/EP1995/002902 patent/WO1996003155A1/de not_active Application Discontinuation
  • 1995-07-24 IL IL11471195A patent/IL114711A0/xx unknown
  • 1995-07-26 ZA ZA956226A patent/ZA956226B/xx unknown

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