EP1017424A1 - Lipophile metall-komplexe für nekrose und infarkt-imaging - Google Patents
Lipophile metall-komplexe für nekrose und infarkt-imagingInfo
- Publication number
- EP1017424A1 EP1017424A1 EP98945248A EP98945248A EP1017424A1 EP 1017424 A1 EP1017424 A1 EP 1017424A1 EP 98945248 A EP98945248 A EP 98945248A EP 98945248 A EP98945248 A EP 98945248A EP 1017424 A1 EP1017424 A1 EP 1017424A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carboxymethyl
- metal complexes
- complexes according
- tris
- dicarboxylic acid
- 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.)
- Withdrawn
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
Definitions
- the invention relates to the subject matter characterized in the claims, i.e. the use of metal complexes which have a plasma protein binding of at least 10% as imaging diagnostics for the localization of an infarction or necrosis as a result of the persistent accumulation of the substances in the infarct or necrosis area.
- the myocardial infarction does not immediately result in an irretrievably inoperable tissue, but initiates a dynamic process that extends over a longer period (weeks to months).
- the disease runs in about three phases, which are not sharply separated, but overlapping.
- the first phase the development of myocardial infarction, comprises the 24 hours after the infarction, in which the destruction progresses like a shock wave (wave front phenomenon) from the subendocardium to the myocardium.
- the second phase the already existing infarction, involves the stabilization of the area in which fiber formation (fibrosis) takes place as a healing process.
- the third phase the healed infarction, begins after all destroyed tissue has been replaced by fibrous scar tissue. Extensive restructuring is taking place during this period.
- necrosis While the infarction is curable to a certain extent, only the harmful consequences for the rest of the organism can be prevented or at least alleviated in the case of necrosis, the locally limited tissue death. Necrosis can arise in many ways: from injuries, chemicals, oxygen deficiency or through radiation. As with an infarction, knowledge of the extent and type of necrosis is important for the further medical procedure.
- infarction and necrosis can be represented by antibodies directed against intracellularly occurring biomolecules and by porphyrins, metalloporphyrins and their derivatives.
- porphyrins metalloporphyrins and their derivatives.
- antibodies and porphyrins can only be produced with great effort and are problematic in handling and compatibility in several respects.
- Metal complexes which have a plasma protein binding of at least 50%, particularly preferably of at least 80%, are particularly suitable.
- the metal complexes according to the invention have a molecular weight of at least 350 Da, preferably at least 400 Da.
- the metal complexes according to the invention are metal derivatives of, for example, polyaminopolycarboxylic acids, polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins, peptides and their derivatives, as described, for example, in “
- the metal must be paramagnetic. This can be one of the transition metals or lanthanides. Suitable ions include those of the elements iron, manganese, gadolinium and dysprosium. If the metal complexes according to the invention are used for radio diagnostics, the metal must be radioactive. This can be an isotope from the series of elements Tc, In, Rh, Ga, Sc, Bi, Y, Fe, Sm, Ho, Co, Cu, Gd, and Eu.
- Suitable chelators are:
- compositions are prepared in a manner known per se by suspending or dissolving the corresponding complex compounds - optionally with the addition of the additives customary in galenics - in an aqueous medium and then, if appropriate, sterilizing the suspension or solution.
- suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), additions of complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or the Ca complexes corresponding to the metal complexes according to the invention) or - if necessary - electrolytes such as sodium chloride or - if necessary - antioxidants such as ascorbic acid.
- suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral or parenteral administration or other purposes, they are mixed with one or more auxiliary agents (for example methyl cellulose, lactose, mannitol) and / or surfactant (s) [for example lecithins, Tween®, Myrj®] and / or flavoring (s) for flavor correction [for example essential oils] mixed.
- auxiliary agents for example methyl cellulose, lactose, mannitol
- surfactant for example lecithins, Tween®, Myrj®
- flavoring for flavor correction [for example essential oils] mixed.
- the invention therefore also relates to processes for the preparation of the complex compounds and their salts.
- the final security is cleaning the isolated complex.
- compositions preferably contain 0.1 ⁇ mol-1 mol / l of the complex and are generally dosed in amounts of 0.0001-5 mmol / kg. They are intended for enteral and parenteral administration.
- the complex compounds are used
- radio diagnostics in the form of its complexes with the radioisotopes of the elements with atomic numbers 27, 29, 31, 32, 37 - 39, 43, 49, 62, 64, 70, 75 and 77.
- the agents meet the diverse requirements for suitability as a contrast agent for magnetic resonance imaging. After oral or parenteral application, they are ideally suited to improve the meaningfulness of the image obtained with the aid of an MRI scanner by increasing the signal intensity. Furthermore, they show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the examinations.
- the good water solubility and low osmolality of the agents make it possible to produce highly concentrated solutions so that the volume of the circulatory system is kept within reasonable limits and the dilution with the body fluid is compensated for. Furthermore, the funds do not have only one high stability in vitro, but also a surprisingly high stability in vivo, so that the release or exchange of the bound to the complexes - toxic to themselves - within the time in which the contrast agents are completely excreted, only extremely slowly.
- the agents for use as NMR diagnostics are dosed in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg. Due to their favorable radioactive properties and the good stability of the complex compounds they contain, the agents are also suitable as radio diagnostic agents. Details of such an application and dosage are e.g. in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.
- the agents When the agents are applied in vivo, they can be administered together with a suitable carrier such as, for example, serum or physiological saline or together with a protein such as, for example, human serum albumin.
- a suitable carrier such as, for example, serum or physiological saline or together with a protein such as, for example, human serum albumin.
- the dosage depends on the type of cellular disorder, the metal ion used and the type of imaging method.
- the agents are usually applied parenterally, preferably IV. As already discussed, they can also be administered intravascularly or interstitially / intracutaneously.
- Renal infarction was induced in anesthetized (Rompun ® / Ketavet®, i.p.) Rats (Han. Wistar, Schering SPF, approx. 200 g body weight) by occlusion of a (caudal) branch of the left renal artery. Contrast agent application (dose: 300 or 500 ⁇ mol Gd / kg body weight) took place approx. 24 h after the infarction induction.
- the anesthetized animals were killed by bleeding (via V. cava) and both kidneys were prepared.
- the left (infarcted) kidney was removed, cut into slices and then an NBT ("vital”) staining was carried out.
- NBT NBT
- the non-perfused portion of the kidney was shown as a hypointense area (see Figure 1 b, 2b). From approx. 15-30 min p. i. the signal intensity in the non-perfused area increased slightly or
- Contrast agent application (stock solution diluted with blood, dose 100 ⁇ mol / kg, iv bolus) was carried out 24 hours after the infarction induction.
- the animals were killed by an anesthetic dose and an MRI experiment was carried out on the “freshly dead” animal (no movement artifacts) in order to verify the infarction (size and location), the heart was prepared, sliced and stained with NBT (nitro blue tetrazolmum chlonde) Subjective assessment of the enhancement and correlation with the colored tissue was carried out.
- the signal intensities were standardized to a Gd-DTPA solution (0.25 mmol / l) and the percentage enhancement Sl post - Sl pre) / Sl pre • 100% and the contrast Sl inf / Sl myocard were calculated
- the maximum enhancement was 100% or 60% immediately after the substance application.
- the signal intensity then decreased and reached a value between 10 and 20% after 150 minutes.
- MS-325 shows suitability as an infarct contrast medium.
Landscapes
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19744004 | 1997-09-26 | ||
DE1997144004 DE19744004C1 (de) | 1997-09-26 | 1997-09-26 | Lipophile Metall-Komplexe für Nekrose und Infarkt-Imaging |
PCT/EP1998/005185 WO1999016474A1 (de) | 1997-09-26 | 1998-08-17 | Lipophile metall-komplexe für nekrose und infarkt-imaging |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1017424A1 true EP1017424A1 (de) | 2000-07-12 |
Family
ID=7844677
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98945248A Withdrawn EP1017424A1 (de) | 1997-09-26 | 1998-08-17 | Lipophile metall-komplexe für nekrose und infarkt-imaging |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1017424A1 (de) |
JP (1) | JP2001518454A (de) |
AU (1) | AU9262898A (de) |
CA (1) | CA2304461C (de) |
DE (1) | DE19744004C1 (de) |
NO (1) | NO321235B1 (de) |
WO (1) | WO1999016474A1 (de) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6482943B1 (en) | 1999-04-30 | 2002-11-19 | Slil Biomedical Corporation | Quinones as disease therapies |
TW462515U (en) * | 1999-08-04 | 2001-11-01 | Chiang Li | Network perfume device |
DE10040381C1 (de) * | 2000-08-11 | 2002-06-06 | Schering Ag | Perfluoralkylhaltige Komplexe mit Zuckerresten, Verfahren zu deren Herstellung und ihre Verwendung |
DE10040858C2 (de) * | 2000-08-11 | 2003-12-18 | Schering Ag | Perfluoralkylhaltige Komplexe mit polaren Resten, Verfahren zu deren Herstellung und ihre Verwendung |
DE102005033903B4 (de) * | 2005-07-15 | 2007-08-09 | Bayer Schering Pharma Ag | Perfluoralkylhaltige Komplexe, Verfahren zu deren Herstellung, sowie deren Verwendung und diese enthaltende pharmazeutische Mittel |
DE102005033902B3 (de) * | 2005-07-15 | 2007-04-05 | Schering Ag | Perfluoralkylhaltige Komplexe, Verfahren zu deren Herstellung, sowie deren Verwendung und diese enthaltende pharmazeutische Mittel |
DE102006049821A1 (de) | 2006-10-18 | 2008-04-24 | Bayer Schering Pharma Aktiengesellschaft | Metallchelate mit perfluoriertem PEG-Rest, Verfahren zu deren Herstellung, sowie deren Verwendung |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4899755A (en) * | 1985-05-08 | 1990-02-13 | The General Hospital Corporation | Hepatobiliary NMR contrast agents |
IT1213029B (it) * | 1986-01-30 | 1989-12-07 | Bracco Ind Chimica Spa | Chelati di ioni metallici paramagnetici. |
IT1224416B (it) * | 1987-12-24 | 1990-10-04 | Bracco Ind Chimica Spa | Chelanti macrociclici e loro chelati |
US5457183A (en) * | 1989-03-06 | 1995-10-10 | Board Of Regents, The University Of Texas System | Hydroxylated texaphyrins |
DE3922005A1 (de) * | 1989-06-30 | 1991-01-10 | Schering Ag | Derivatisierte dtpa-komplexe, diese verbindungen enthaltende pharmazeutische mittel, ihre verwendung und verfahren zu deren herstellung |
WO1994001393A1 (en) * | 1992-07-03 | 1994-01-20 | The Green Cross Corporation | Novel chelating agent, complex compound composed of said agent and metallic atom, and diagnostic agent containing said compound |
US5358704A (en) * | 1993-09-30 | 1994-10-25 | Bristol-Myers Squibb | Hepatobiliary tetraazamacrocyclic magnetic resonance contrast agents |
US5582814A (en) * | 1994-04-15 | 1996-12-10 | Metasyn, Inc. | 1-(p-n-butylbenzyl) DTPA for magnetic resonance imaging |
EP0758907A1 (de) * | 1994-05-11 | 1997-02-26 | Schering Aktiengesellschaft | Verwendung von porphyrinkomplexen oder vergrösserten porphyrinkomplexen als diagnostikum für die lokalisierung von infarkt oder nekrose |
TW319763B (de) * | 1995-02-01 | 1997-11-11 | Epix Medical Inc | |
DE19603033A1 (de) * | 1996-01-19 | 1997-07-24 | Schering Ag | Perfluoralkylhaltige Metallkomplexe, Verfahren zu deren Herstellung und ihre Verwendung in der NMR-Diagnostik |
WO1997030734A1 (en) * | 1996-02-21 | 1997-08-28 | Mallinckrodt Medical, Inc. | Magnetic resonance blood pool agents |
AU4753997A (en) * | 1996-10-16 | 1998-05-11 | Burnham Institute, The | Magnetic resonance imaging of thrombi |
-
1997
- 1997-09-26 DE DE1997144004 patent/DE19744004C1/de not_active Expired - Fee Related
-
1998
- 1998-08-17 AU AU92628/98A patent/AU9262898A/en not_active Abandoned
- 1998-08-17 WO PCT/EP1998/005185 patent/WO1999016474A1/de active Application Filing
- 1998-08-17 CA CA002304461A patent/CA2304461C/en not_active Expired - Fee Related
- 1998-08-17 EP EP98945248A patent/EP1017424A1/de not_active Withdrawn
- 1998-08-17 JP JP2000513606A patent/JP2001518454A/ja active Pending
-
2000
- 2000-03-23 NO NO20001520A patent/NO321235B1/no not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
See references of WO9916474A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2304461A1 (en) | 1999-04-08 |
WO1999016474A1 (de) | 1999-04-08 |
CA2304461C (en) | 2008-10-14 |
NO20001520D0 (no) | 2000-03-23 |
JP2001518454A (ja) | 2001-10-16 |
NO20001520L (no) | 2000-05-25 |
NO321235B1 (no) | 2006-04-10 |
DE19744004C1 (de) | 1999-07-22 |
AU9262898A (en) | 1999-04-23 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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Effective date: 20000129 |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BAYER SCHERING PHARMA AG |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT |
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17Q | First examination report despatched |
Effective date: 20080903 |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BAYER PHARMA AKTIENGESELLSCHAFT |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 20091009 |