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WO1996038183A1 - Milieu de contraste et son utilisation - Google Patents

Milieu de contraste et son utilisation Download PDF

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Publication number
WO1996038183A1
WO1996038183A1 PCT/US1996/007666 US9607666W WO9638183A1 WO 1996038183 A1 WO1996038183 A1 WO 1996038183A1 US 9607666 W US9607666 W US 9607666W WO 9638183 A1 WO9638183 A1 WO 9638183A1
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WO
WIPO (PCT)
Prior art keywords
cells
contrast medium
protecting
agent
contrast
Prior art date
Application number
PCT/US1996/007666
Other languages
English (en)
Inventor
Rafi Korenstein
Avi Dascalu
Original Assignee
Israel Humanitarian Foundation Ltd.
Jade Holding Inc. B.V.I.
Harell, Avikam
Shoshan, Herbert, Z.
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 Israel Humanitarian Foundation Ltd., Jade Holding Inc. B.V.I., Harell, Avikam, Shoshan, Herbert, Z. filed Critical Israel Humanitarian Foundation Ltd.
Priority to US08/952,954 priority Critical patent/US6149891A/en
Priority to AU59309/96A priority patent/AU707118B2/en
Priority to EP96916620A priority patent/EP0863770A4/fr
Publication of WO1996038183A1 publication Critical patent/WO1996038183A1/fr

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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
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0452—Solutions, e.g. for injection
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers

Definitions

  • the present invention is generally in the field of contrast media. More specifically, the present invention relates to a contrast medium with improved patient's tolerance.
  • Contrast Media are routinely used in various imaging procedures. Such procedures include visualization of blood vessels in cardiac angiography, either by x-ray imaging or by Magnetic Resonance Imaging (MRI), intravenous urography (kidney imaging), computerized tomography and neurologic visualization of the spinal cord, the brain, etc.
  • MRI Magnetic Resonance Imaging
  • Kidney imaging intravenous urography
  • computerized tomography neurologic visualization of the spinal cord, the brain, etc.
  • CM Contrast Media
  • CM in the x-ray imaging procedure can be grouped, on the basis of their osmolarity, to such which have a low osmolarity (hereinafter "LOCN”) and such having a high osmolarity (hereinafter "HOCM”).
  • LOCN low osmolarity
  • HOCM high osmolarity
  • both LOCM and HOCM have an osmolarity which is above that of the blood.
  • HOCM have a typical osmolarity of about 1500 - 2000 mOsm/kg
  • LOCM have an osmolarity within the range of 300 - 700 mOsm/kg.
  • Adverse side effects associated with CMs include such which result from the high osmolarity.
  • the visualization which is the outcome of CM injection into the blood, results from a local dispersion of the high iodine atom concentration contained in the CM, from the high osmolarity, as well as from an increased viscosity in the blood vessels of the visualized organ (2) .
  • this is achieved either by injection into the blood vessels or by catheterization.
  • the MRI method for visualization of blood vessels comprises the injection of a paramagnetic substance dissolved in a hyperosmotic CM to the region to be visualized.
  • Hyperosmotic damage Typically 100-200 ml of CM are injected into a total plasma volume of 5 liters within a period of several minutes. Cells such as endothelial cells, red and white blood cells, cells within the kidney, etc., are exposed to a hyperosmotic solution, reaching 200-2000 mOsm/kg at the site of injection, as compared to the osmolarity of the blood with its 300 mOsm/kg, giving rise to a hyperosmotic shock which may elicit related damages.
  • hyperosmotic CM will refer to any CM having osmolarity higher than the blood osmolarity which is typically 300 mOsm/kg.
  • Iodine specific toxicity In an x-ray visualization procedure typically 30- 40 grams of iodine (included within the contrast media) are injected into the blood within the period of 2-10 minutes. It should be noted that target visualization requires a minimum accumulation of 15-20 mg of iodine/ml in the target tissue (3) and this is the reason that the initial iodine concentration in the CM is relatively high in the range of 300-420 mg iodine/ml.
  • Kidney damage The iodine load to which the kidney is exposed and which it has to secrete is a potential cause for renal damage (4) . It is generally believed today that 12% of all patients which are injected with an x-ray CM, encounter renal complications ⁇ . A recent study shows that during cardiac catheterization procedure, 9% of low risk and 16% of high risk patients develop renal failure (6 ⁇ Various studies made with CMs have shown that exposure of cells to x-ray CM causes the cell damages (7 ' 8 ' 9 - 10) .
  • the term "contrast agent” or "CA” will be used to denote an agent which absorbs or reacts in another way with the electromagnetic irradiation used in a body visualization procedure.
  • the CA which is injected into the circulation, may be an agent, such as an iodine containing substance, which blocks x-ray irradiation and can thus be used for the visualization of blood vessels or other body fluid-containing organs or tissue in x-ray visualization procedure.
  • the CA may also be a paramagnetic substance used in an MRI visualization procedure.
  • CM contrast medium
  • CA contrast medium
  • protecting agent or "PA” will be used to denote an agent which in accordance with the present invention is incorporated into a CM, for the purpose of protecting tissue or organs, fully or partially, against some or all of the hazardous effects of CM's noted above.
  • the CM in accordance with the present invention thus comprises both a CA and a PA.
  • effective amount will be used to denote an amount of an agent sufficient to achieve the desired effect.
  • the effective amount is an amount sufficient to achieve the desired contrast.
  • an effective amount is an amount sufficient to achieve a protecting effect.
  • a contrast medium comprising an effective amount of a contrast agent, and an effective amount of a protecting agent being an agent active in protecting against possible damaging effects of the contrast medium, said protecting agent being one or more members selected from the group consisting of (i) non-steroidal anti-inflammatory drugs (NSAID), (ii) agents which induce cells to generate nitrous oxides (NO), (iii) polysaccharides capable of sealing the intercellular spaces which exist between endothehal cells, (iv) direct anticoagulants of the heparin class and (v) antioxidants which are free radical scavengers.
  • NSAID non-steroidal anti-inflammatory drugs
  • NO nitrous oxides
  • iii polysaccharides capable of sealing the intercellular spaces which exist between endothehal cells
  • direct anticoagulants of the heparin class and antioxidants which are free radical scavengers.
  • the present invention further provides, by a second of its aspects, use of said protecting agents in the preparation of a contrast medium.
  • the invention still further provides, by a third of its aspects, a method for protecting an individual against harmful effects of a CM, comprising administering to the individual, together with the contrast medium, also a protecting agent as defined above.
  • NSAID non-steroidal anti-inflammatory drugs
  • Aniline derivatives such as paracetamol, phenacetin;
  • Anthranilic derivatives such as flufanamic acid, mefenamic acid;
  • Phenyl alkanoic derivatives such as fenoprofen, flurbiprofen, ibufrofen, ketoprofen;
  • Pyrazole derivatives such as amidopyrine. dipyrone, phenazone, phenylbutazone; Salicylic acid derivatives such as aspirin, salicylic acid, choline salicylate.
  • agents which induce cells to generate nitrous oxide (NO) are nitroglycerine, nitroprusside, isosorbide dinitrate and others.
  • Polysaccharides which act in sealing the intercellular spaces between endothehal cells are agents capable of forming a coating over the walls of blood vessels and of forming a barrier between the interior of the blood vessel and the cells.
  • An example of such an agent is dextran.
  • Examples of direct anti-coagulants of the heparin class are: heparin, low molecular weight heparins (such as inoxaprine) and the like.
  • Anti-oxidants which are free radical scavengers are useful particularly where the CA is of a kind that is capable of inducing the formation of free radicals which cause cellular damage. Examples for such agents are glutathione, tocopherols and the like.
  • Fig. 1 shows the effect of CA (added at tj and t 2 ) on intracellular calcium endothehal cells in vitro.
  • Fig. 2 demonstrates the effect of the combination of PA and CA upon the intracellular calcium (CA and PA were added together at t x then washed and then CA was added separately at t 2 ).
  • HUVEC Human umbilical vascular endothehal cells
  • CRL-1730 American Type Culture Collect
  • F 12K medium Irving Scl. USA
  • Endothehal Cell Growth Factor 100 ⁇ g/ml heparin
  • 10% fetal calf serum 10% fetal calf serum
  • neonatal calf serum 10% fetal calf serum
  • Cells were seeded at an initial density of 1-2 x 10 5 cells/cm 2 and kept at 37 ° C under an atmosphere of 5% CO, in air.
  • [Ca +2 ] analysis was performed by using an Applied Imaging Magical system (TARDIS version 7.3). Cover slips with attached endothehal cells in the epifluorescence mode (oil-immersion objective, X 40) and equipped with a xenon lamp. Intracellular calcium measurements were assayed by ratio imaging of FURA-2/AM (excitation, 340 and 380 nm; emission, 515 nm). A temperature-controlled cell perfusion chamber (Applied imaging) was used to keep cells at a temperature of 32 ° C. All solutions were maintained at 32 ° C in a temperature controlled bath. Single cell images (10-40 cells) were collected by an intensified video camera (Photonic Science).
  • Intracellular calcium calibration Fura-2/AM signals were calibrated by addition of lonomycin (5 ⁇ M) to cells kept in a 2 mM Ca +2 solution to obtain maximum fluorescence. An addition of 10 mM of [ethylene-bis- (oxyethylenenitrilo)]-tetraacetic acid) (EGTA) followed in order to adjust the pH to > 8.5 in order to obtain the minimal fluorescence.
  • EGTA ethylene-bis- (oxyethylenenitrilo)]-tetraacetic acid
  • the intracellular calcium was calculated as previously described employing a Ca +2 - Fura 2 dissociation constant of 224 nM.
  • the 3-[4,5-Dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) colorimetric reaction is based on the uptake of tetrazolium salt exclusively by live cells and its reduction to a soluble violet (formazan) compound. Absorbance of formazan is proportional to the amount of active mitochondrial enzyme succinate-dehydrogenase of the cells and consequently to cell viability. Both endothehal or kidney cells were seeded at 30000-40000 cells/well in 96-well microliter wells (Corning) and grown until confluence.
  • the measurements were performed after statistically testing the assumption that endothehal cells as well as the kidney cell line display contact inhibited cell growth, therefore yielding about equal cell numbers in each well.
  • the absorbance spectrum of MTT was determined by a diode array spectropho- tometer (Hewlett Packard, 8452A). MTT exhibited peak absorbance at 560 nm and minimal readings beyond 620 nm, as previously shown.
  • a microplate reader (Thermomax, Molecular Devices) was used to read absorbance at 550 nm with background subtraction at a reference absorbance of 650 nm at 25 ° C.
  • the effect of using PA in conjunction with CA materials was evaluated by determining the cytotoxic effect and intracellular calcium levels in endothehal cells with or without PA.
  • the effect of CA in this case TelebrixTM, (Guerbet, France)
  • Fig. 1 As can be seen, upon addition of 35 ⁇ l of CA into 1 ml of hepes-buffered saline at t lf there is an immediate increase in the intracellular calcium level. The calcium level increase also occurs upon re-addition of the same CA at t 2 .
  • a CA as described above was administered together with indomethacin, as shown in Fig. 2 (at t : ), there was no or negligible increase in the intracellular calcium level.
  • CAl Ultravist, Schering, AG, Germany
  • CA2 Hexabrix-320, Guerbet, France
  • CA3 Omnipaque, Schering AG, Germany
  • CA4 Conray-60, Malinckrodt, U.S.A.
  • A Indomethacin (50 micromolar)
  • B Heparin (100 units/ml)
  • C Dextran (50 microgram/ml)
  • D Nitroprusside (50 micromolar)
  • E Glutathione (2 mM).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Food Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention se rapporte à un milieu de contraste qui renferme une quantité efficace d'agents de contraste et d'un agent de protection, lequel protège activement l'usager contre d'éventuels effets néfastes induits par le milieu en question.
PCT/US1996/007666 1995-05-31 1996-05-24 Milieu de contraste et son utilisation WO1996038183A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US08/952,954 US6149891A (en) 1995-05-31 1996-05-24 X-ray contrast medium and method for protecting against harmful effects thereof
AU59309/96A AU707118B2 (en) 1995-05-31 1996-05-24 Contrast medium and its use
EP96916620A EP0863770A4 (fr) 1995-05-31 1996-05-24 Milieu de contraste et son utilisation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL113926 1995-05-31
IL11392695A IL113926A (en) 1995-05-31 1995-05-31 Contrast medium with improved patient's tolerance thereto and its use

Publications (1)

Publication Number Publication Date
WO1996038183A1 true WO1996038183A1 (fr) 1996-12-05

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ID=11067540

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/007666 WO1996038183A1 (fr) 1995-05-31 1996-05-24 Milieu de contraste et son utilisation

Country Status (5)

Country Link
EP (1) EP0863770A4 (fr)
AU (1) AU707118B2 (fr)
CA (1) CA2222429A1 (fr)
IL (1) IL113926A (fr)
WO (1) WO1996038183A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE34077E (en) * 1988-05-02 1992-09-22 Cryomedical Sciences, Inc. Blood substitute
US5199951A (en) * 1990-05-17 1993-04-06 Wayne State University Method of drug application in a transporting medium to an arterial wall injured during angioplasty
US5334370A (en) * 1993-02-04 1994-08-02 Sterling Winthrop Inc. Compositions of alkylbenzenes in film-forming materials for visualization of the gastrointestinal tract

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2191118A (en) * 1937-06-03 1940-02-20 Firm Of N V Orgachemia Pyelographic preparation
US2870063A (en) * 1955-07-05 1959-01-20 Mallinckrodt Chemical Works X-ray contrast composition comprising substantially amylose-free amylopectin in aqueous solution of contrast agent
US3984571A (en) * 1970-03-10 1976-10-05 E. R. Squibb & Sons, Inc. Hydrocolloid containing liquid carrier for a diagnostic or therapeutic agent
US5847009A (en) * 1986-01-14 1998-12-08 Alliance Pharmaceutical Corp. Prophylaxis in the parenteral administration of particulate dispersions in fluorocarbon emulsions
FR2635327B1 (fr) * 1988-08-10 1990-11-16 Guerbet Sa Polymeres iodes, a squelette dextrane, leurs procedes de preparation et leurs applications comme produits de contraste
US5019370A (en) * 1989-07-10 1991-05-28 University Of Kentucky Research Foundation Biodegradable, low biological toxicity radiographic contrast medium and method of x-ray imaging
DE19518221A1 (de) * 1995-05-10 1996-11-14 Schering Ag Verwendung nichtsteroidaler Entzündungshemmer zur Verbesserung der physiologischen Verträglichkeit partikulärer pharmazeutischer Zubereitungen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE34077E (en) * 1988-05-02 1992-09-22 Cryomedical Sciences, Inc. Blood substitute
US5199951A (en) * 1990-05-17 1993-04-06 Wayne State University Method of drug application in a transporting medium to an arterial wall injured during angioplasty
US5334370A (en) * 1993-02-04 1994-08-02 Sterling Winthrop Inc. Compositions of alkylbenzenes in film-forming materials for visualization of the gastrointestinal tract

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRITISH MEDICAL BULLETIN, Volume 50, Number 4, issued October 1994, VERSTRAETE, "Primary and Secondary Prevention of Arterial Thromboembolism", pages 946-965. *
See also references of EP0863770A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

Also Published As

Publication number Publication date
AU707118B2 (en) 1999-07-01
AU5930996A (en) 1996-12-18
IL113926A (en) 2000-06-01
IL113926A0 (en) 1995-08-31
EP0863770A4 (fr) 2001-01-10
CA2222429A1 (fr) 1996-12-05
EP0863770A1 (fr) 1998-09-16

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