CN1238698A - Method - Google Patents

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CN1238698A
CN1238698A CN 97180009 CN97180009A CN1238698A CN 1238698 A CN1238698 A CN 1238698A CN 97180009 CN97180009 CN 97180009 CN 97180009 A CN97180009 A CN 97180009A CN 1238698 A CN1238698 A CN 1238698A
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contrast medium
manganese
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radiography
arbitrary
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G·佩特尔松
K·戈尔曼
A·雅各布森
L·I·奥德加尔德斯图恩
A·K·法尔维克
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GE Healthcare AS
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Nycomed Imaging AS
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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
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • 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

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  • 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)
  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

The invention provides the use of a physiologically tolerable manganese compound or a salt thereof, substantially free from hydrophilic polymer components containing a significant amount of a Mn<2+>- chelating unit, in the manufacture of an enterally, e.g. orally or rectally, administrable MRI contrast medium composition for use in a method of imaging of a human or non-human animal body which has fasted for a period of at least 6, preferably at least 10, more preferably at least 12 hours before enteral administration of said composition. It has been found that diagnostically effective levels of uptake of orally or rectally administered manganese may be achieved using this method.

Description

Method
The present invention relates to the improvement or the improvement relevant of nuclear magnetic resonance (MRI), particularly relate to manganese compound is used for the radiography contrast medium (constract media) of abdominal part imaging in preparation purposes with nuclear magnetic resonance.
Now, MRI is a kind of very sophisticated medical diagnostic method.Can produce the high-quality image and can distinguish different soft tissues and the technology that do not need patient to be exposed in the ionizing radiation contributes for the success of MRI.
Just can not implement MRI though do not use additional radiography contrast medium, but have been found that the material that can influence atomic nucleus (being called " imaging nuclear "-be often referred to water proton in body fluid and tissue hereinafter) nuclear spin reequilibrate can be used for strengthening the video contrast, and correspondingly, there were many this materials to be proposed in recent years as MRI radiography contrast medium, wherein magnetic resonance signal is produced by atomic nucleus, and image produces from magnetic resonance signal.
The enhancing contrast of using the radiography contrast medium to obtain by increasing or reducing the signal level of specific organ or tissue with respect to its surrounding, can make clearer that specific organ or tissue manifests.Increase target site and be called " positivity " radiography contrast medium, be called " negativity " radiography contrast medium with respect to the radiography contrast medium of the signal level of its surrounding and reduce target site with respect to the radiography contrast medium of the signal level of its surrounding.
The contrast of radiography between the inherent tissue of some problem, particularly abdominal part is very weak, and lacks especially effective radiography contrast medium and hindered MRI as gastrointestinal tract (g.i.) or in fact be often referred to the development of abdominal part imaging technique.
Now just planning to obtain contrast effect, because they contain paramagnetism, superparamagnetism or ferromagnetism class material as most of materials of MRI radiography contrast medium.
Paramagnetism radiography contrast medium both can be that positivity MRI radiography contrast medium also can be a negativity MRI radiography contrast medium.Paramagnet depends on many factors to the influence of magnetic resonance signal intensity, most important factor be paramagnet the characteristic of the concentration in imaging site, paramagnet itself and pulse train and in radiography used magnetic field intensity.Yet usually when using with low concentration, its T1 weakens effect when dominant, and paramagnetism radiography contrast medium is a positivity MRI radiography contrast medium, when use its T with higher concentration 2(or T 2*) weaken effect when dominant, paramagnetism radiography contrast medium is a negativity MRI radiography contrast medium.
The example that known physiology as MRI radiography contrast medium can tolerate paramagnet is a manganese ion, and manganese ion is convenient to use with the form of its salt or chelate.Yet,, cause forming deformity with clinical dosage administration meeting when manganese during as radiography contrast medium intravenous administration.Behind the intravenously administrable, by the calcium in the displacement heart calcium pump, manganese can also disturb the normal function of heart.
In order to reduce the direct effect to heart, the someone proposes the manganese oral administration.The result of upper gastro-intestinal tract vascularization is that the material of oral administration flow in the liver earlier before flowing into heart after enteral absorbs the blood.Concerning manganese, in liver, can be prevented that by the hepatocyte absorption manganese from reaching the cardiotoxicity level in heart.Therefore hepatocyte means that to the picked-up of manganese the manganese of oral administration can be as the magnetic resonance radiography contrast medium of liver.
Yet, in the zoopery in early days,, do not have to find MnCl to oral administration when manganese during with clinical relevant dose administration 2See through effectively picked-up of intestinal wall diagnosis.And, behind the oral administration, contain the gastrointestinal tract magnetic resonance radiography contrast medium of manganese, for example manganese/hydrophilic polymer composition Lumenhance except in the inclusions of intestinal, does not show the effect of any enhancing image.
Therefore, in order to obtain diagnosis from intestinal effectively is the manganese of radiography effective dose, need to use the material that can promote effectively that manganese absorbs, W-A-96/05867 proposes a solution manganese and absorbs insufficient method, be in intestinal manganese radiography contrast medium and one or more picked-up promoter to be united use, said picked-up promoter can promote manganese to pass the transportation of gastrointestinal tract film.The example of this picked-up promoter comprises ascorbic acid and kojic acid.
Yet, use the magnetic resonance image method of manganese radiography contrast medium still to need to improve, particularly for the abdominal part imaging, for example liver and gastrointestinal tract are all the more so.
Now, we are surprised to find, to the picked-up of the manganese of oral or rectally diagnosis effect level, and can be by guaranteeing in intestinal without any food or not comprising a large amount of Mn 2+-sting and close unitary hydrophilic polymer and manganese and exist simultaneously and easily reach, for example, with manganese chloride administration after fasting a period of time." in a large number " is meant Mn 2+-sting the amount height of the unit of closing to the degree that can influence the manganese picked-up.
Although be not wishing to be bound by theory, it is believed that to have food in the intestinal, particularly exist to contain and contain a large amount of Mn in hydrophilic polymer composition and the hydrophilic polymer 2+-to sting when closing unitary food, food will form complex closely with manganese ion, has therefore hindered the transportation that manganese passes the gastrointestinal tract film.
Therefore, from one side, the invention provides physiology and can tolerate manganese compound or its salt and making the enteral administration, the purposes in the MRI radiography contrast medium compositions of for example oral or rectally, wherein said manganese compound or its salt are substantially devoid of and comprise a large amount of Mn 2+-sting and close unitary hydrophilic polymer component, described radiography contrast medium compositions is used in the angiographic method of a kind of people or non-human animal's body, wherein before the administration of compositions enteral, and human body or the fasting of non-human animal's body elder generation at least 6 hours, preferably at least 10 hours, more preferably at least 12 hours.
Fasting means that in specified time limit not edible any may containing comprises Mn 2+-sting the food that closes unit, particularly solubility or fibrous hydrophilic polymer component.During fasting, can take water or sugar.
In a particularly preferred embodiment according to the invention, manganese radiography contrast medium is without any for example administration under the ascorbic acid situation about existing of picked-up promoter basically.
In the embodiment of a selection, the invention provides a kind of by this radiography contrast medium rectally being obtained the method for liver and the enhanced image of hindgut.Because the special vascularization of hindgut can directly not enter heart earlier after the manganese of some rectally absorbs by liver.Yet we are surprised to find, and by manganese rectally that will be very low dose of, can obtain effective intake of manganese in hindgut, can produce the enhanced especially image of liver and hindgut.This to detect the hindgut lump for example diagnosing colon cancer have special value.
From another point of view, the invention provides physiology and can tolerate manganese compound or the purposes of its salt in the MRI radiography contrast medium compositions of making rectally, wherein said manganese compound or its salt are substantially devoid of and comprise a large amount of Mn 2+-to sting and close unitary hydrophilic polymer component, described radiography contrast medium compositions is used in the angiographic method of a kind of human body or non-human animal's body, is substantially devoid of during the inherent imaging of the gastrointestinal tract of wherein said people or non-human animal's body to comprise a large amount of Mn 2+-sting the hydrophilic polymer composition of the unit of closing.For the purpose of convenient, with this radiography contrast medium compositions to fasting at least 6 hours, preferably at least 10 hours, more preferably at least 12 hours human body or the administration of non-human animal's body.
The flushing colon is to guarantee wherein to be substantially devoid of any a large amount of Mn that comprise in advance 2+-sting and close unitary hydrophilic polymer, behind the manganese rectally, just can obtain the maximum ingestion amount of manganese.In case any undesirable hydrophilic polymer composition is eliminated totally in intestinal, manganese just can be ingested and produce image in intestinal.
Rectally can be with the rectum insertion tube that the radiography contrast medium is given to selected zone in the intestinal being carried out.
Manganese compound is convenient to be present in the radiography contrast medium compositions with the concentration of 0.3mM at least, or non-that are this, contains the manganese of at least 300 μ mol in a dosage unit form.
The manganese compound that is used for oral administration preferably dissolves in gastro-intestinal Fluid, can be for example chelate or salt, maybe can be the mixture of different salt and/or chelate.Particularly preferably be metallo-chelate and salt, wherein manganese exists with bivalent manganese rather than manganic form, because the former has higher magnetic moment and is more effective MRI radiography contrast medium therefore.
The example that is particularly suitable for the manganese compound that uses according to the present invention comprises manganese chloride, Manganese ascorbate and kojic acid manganese.
Manganese compound is convenient to unite use, the picked-up promoter of for example describing with one or more picked-up promoter in WO-A-96/05867.In this case, radiography contrast medium compositions can with picked-up promoter with the form administration of compound preparation, or non-that are this, before the administration of picked-up promoter, during the administration or after the administration that radiography contrast medium compositions is individually dosed.On the other hand, manganese compound can administration under the situation of not absorbing promoter basically.
Suitable picked-up promoter comprises, contains an Alpha-hydroxy ketone group and (the reproducibility chemical compound of CH (OH)-CO-), contains α-and/or beta-hydroxy or amino acid, vitamin D and its mixture.The reproducibility of picked-up promoter is very important, because compare with manganic, intestinal more trends towards absorbing bivalent manganese to the normal picked-up of manganese.
Described herein " contain α-and/or beta-hydroxy or amino acid " comprises and contains collagen-hydroxyl or former-amino aromatic acid.
Preferred picked-up promoter comprises reproducibility chemical compound recited above, further contain oxygen atom in heterocycle structure.
Particularly preferred picked-up promoter is ascorbic acid, has been found that and MnCl 2Oral administration is compared separately, and ascorbic acid can make the picked-up of manganese in gastrointestinal tract increase about 5 times.And ascorbic acid (vitamin C) is very cheap, can obtain easily and can be tolerated particularly well by health.When oral administration, ascorbic acid also helps to cover up the metallic taste of manganese, has therefore improved the taste of radiography contrast medium.
Kojic acid also is preferably to absorb promoter.
Have been found that and to comprise carboxylic acid as the example of the acid of especially effectively absorbing the promoter use, for example gluconic acid and salicylic acid.Also find α-and beta-amino acids can be effectively as picked-up promoter, a-amino acid particularly, for example alanine, glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine, especially arginine, lysine and aspartic acid.
For the purpose of convenient, manganese is 1 with the mol ratio of picked-up promoter: 0.2-1: 50, for example 1: 1-1: 20, particularly 1: 1-1: 10, more preferably 1: 1-1: 8, and can also be more preferably 1: 1-1: 6, especially 1: 2-1: 6, preferred about 1: 5 especially.
On the other hand, manganese can be 1 with the mol ratio of picked-up promoter: 1.5-1: 5, for example 1: 1.5-1: 4, particularly 1: 2-1: 4, especially 1: 2-1: 3, and preferred about 1: 2 especially.
If necessary, picked-up promoter can be whole or in part exists with the form of the gegenion of manganese ion.Therefore in a specific embodiments, manganese compound used according to the invention comprises the manganese salt of the reproducibility chemical compound with Alpha-hydroxy ketone group, or has α-and/or the manganese salt of beta-hydroxy or amino acid, for example Manganese ascorbate (II) or manganese salicylate.
As mentioned above, paramagnetic material for example manganese ion both can be used as positivity MRI radiography contrast medium, can be used as negativity MRI radiography contrast medium again, and this depends on many factors, comprised concentration and the radiography employed magnetic field intensity of ion in the imaging site.According to the concentration of final manganese ion in gastrointestinal tract, can for example produce signal suppressing or enhancement effect.Therefore can obtain " double contrast radiograph effect " and marginal definition along with the concentration change of manganese like this.
Although think that the wide range of concentrations of manganese is in protection domain of the present invention; but two preferred concentration range are arranged usually; one is the concentration range that can obtain strong negativity radiography between muscular tissue around the harmonization of the stomach, and another is the concentration range that can obtain strong positivity radiography.For the negativity radiography, for the purpose of making things convenient for, the concentration of manganese is greater than 10mM, preferred 10mM-50mM.For the positivity radiography, for the purpose of making things convenient for, the concentration of manganese is 0.1mM-10mM, preferred 1mM-6mM.
When using the radiography contrast medium to obtain the double contrast radiograph effect, wherein bag does not produce artificial image when not containing the radiography contrast medium in intestinal, need add viscosity-increasing agent and/or osmotically active agent in the radiography contrast medium, and they are not to comprise a large amount of Mn 2+-sting and close unitary hydrophilic polymer.The example of suitable viscosity-increasing agent and osmotically active agent was described in WO-A-91/01147 and WO-A-91/01148.
This radiography contrast medium compositions also can be united use with another kind of radiography contrast medium, preferred a kind of radiography contrast medium that can be retained in the intestinal and show negativity radiography effect.Can produce the double contrast radiograph effect like this, the radiography of abdominal part and marginal definition are strengthened especially.In this case, this radiography contrast medium can with the form administration of another kind of radiography contrast medium with compound preparation.On the other hand, another kind of radiography contrast medium also can be before the radiography contrast medium administration that contains manganese, during the administration or is individually dosed after the administration.
From another aspect, therefore the present invention provides physiology can tolerate manganese compound or its salt and the another kind of purposes of radiography contrast medium in making MRI radiography contrast medium compositions that can produce negativity radiography effect in intestinal, and wherein said manganese compound or its salt are substantially devoid of and comprise a large amount of Mn 2+-sting and close unitary hydrophilic polymer, described radiography contrast medium compositions is used in the angiographic method of a kind of human body or non-human animal's body, compositions while, independent or successive administration, before the administration of described radiography contrast medium compositions enteral, human body or the fasting of non-human animal's body at least 6 hours, preferably at least 10 hours, more preferably at least 12 hours.
According to the concentration of manganese, the radiography contrast medium that contains manganese both can play the effect of positivity radiography contrast medium, also can play the effect of negativity radiography contrast medium.Usually, when using with the concentration of being planned to adopt according to the present invention, the radiography contrast medium that contains manganese will play positivity radiography contrast medium.Therefore for the purpose of convenient, another kind of radiography contrast medium is a negativity radiography contrast medium, and can be any negativity MRI radiography contrast medium that is suitable for the enteral administration.
For the purpose of convenient, in another kind of radiography contrast medium, do not conform to basically to have and comprise a large amount of Mn 2+-sting and close unitary hydrophilic polymer.
The method according to this invention and the example of the negativity MRI radiography contrast medium that uses comprises known ferromagnetism and superparamagnetism radiography contrast medium, for example AMI 227, the SINEREM that from advanced person's magnetic material, obtains, and ferric oxide particles, wherein said ferric oxide particles both can individualism, also can be enclosed in or in conjunction with last non magnetic host material, for example the magnetic polymer particles that can buy by trade name LUMIREM (Guerbet SA) and ABDOSCAN (Nycomed Imaging AS).
The method according to this invention and the other example of another kind of radiography contrast medium that uses comprises Gd and the Dy that is combined on the polymeric matrices, the radiography contrast medium that can buy by trade name GADOLITE (aluminosilicate gadolinium oral suspension) for example, the radiography contrast medium that can from Pharmacyclic, obtain.Further example comprises known sensitive agent, and for example insoluble barium compound is used for the radiography contrast medium commonly used of barium meal or barium coloclysis when for example barium sulfate and other carry out X-ray examination to intestinal.
Since also there is manganese in the gastrointestinal tract, so another kind of radiography contrast medium obtains the required amount of negativity image and may quite lack in intestinal, required amount when for example there is not manganese in 1/10-1/2.
When using manganese composition according to the present invention to reach the double contrast radiograph effect, particularly preferably be in the radiography contrast medium and add viscosity-increasing agent, this viscosity-increasing agent is not to comprise a large amount of Mn 2+-to sting and close unitary hydrophilic polymer, it only is just can reach viscosity-increasing effect completely after the administration of radiography contrast medium.The radiography contrast medium therefore can be with the form picked-up that quite can tolerate, and the while is in the site that is prepared to picture or reaching required viscosity in the process in imaging site.
The example of the negativity radiography contrast medium that other is suitable for using according to the present invention comprises gas, gas generation agent or is filled with the granule of gas.Therefore, another kind of radiography contrast medium can discharge for example CO of gas after can comprising oral administration 2Or N 2Gas generate agent.Preferred gas generates agent, and to be those with gastric juice in the stomach contact can discharge CO 2Or N 2Gas generate agent.On the other hand, if wish to delay the release of gas, gas can be generated agent and wrap that undissolved coating reaches this purpose when contacting with gastric juice.The example that is suitable for coming using gases to generate agent according to the present invention comprises MnCO 3, NaCO 3And NaHCO 3
In embodiment preferred of the present invention, the rectally of radiography contrast medium can be blown to unite and be carried out to obtain enhanced especially double contrast radiograph effect with rear intestinal.For the purpose of convenient, air blowing can be by being blown into gas, for example air, CO in postcolon in the administration of radiography contrast medium or after the administration 2Or N 2Finish.Like this, be full of gas in the cavity of postcolon, and manganese radiography contrast medium covers intestinal wall.In the MR image that obtains, the cavity blackening of colon, intestinal wall and liver are very bright.
One of problem that abdominal part imaging, particularly gastrointestinal tract imaging run into is, because the physiological movement of imaging region, the MR signal intensity is tending towards changing.By adopting the fasting imaging method, can overcome this problem to a certain extent.Can imaging in being less than 20 seconds intervals (therefore can one " holding one's breath " at interval in imaging) technology be preferred use in the method according to the invention.Specially suitable technology comprises the spin echo operation, and (TR=80-150ms is TE=10-14ms) with gtadient echo operation (TR ≈ 50ms, TE-4ms, flip angle=80-90 °).Gtadient echo is operated preferably choked flow.
The radiography contrast medium compositions of using among the present invention re-uses (if necessary) after being particularly suitable for disperseing in aqueous medium, to carry out the radiography of abdominal part, particularly stomach, intestinal, liver, bile duct and gallbladder.In order to reach the radiography effect, the radiography contrast medium can be administered in the gastrointestinal tract by oral, rectum or through stomach tube.Method of the present invention can produce high-quality abdominal part 3-dimensional image, particularly liver 3-dimensional image.Provide show the intestinal wall structure know that aspect the image, method of the present invention also has good especially value, therefore can detect any abnormal conditions in the intestinal wall.
From another aspect, therefore the present invention provides people or non-human animal, produce the method for magnetic resonance image in the preferred mammal body, comprise and physiology can be tolerated manganese compound or its salt is administered in the gastrointestinal tract of said health, produce the image at said health radiography position, wherein manganese compound is substantially devoid of and comprises a large amount of Mn 2+-sting and close unitary hydrophilic polymer, before the administration, described human body or the fasting of non-human animal's body elder generation at least 6 hours, preferably at least 10 hours, more preferably at least 12 hours.
Again from another point of view, the invention provides people or non-human animal, produce the method for magnetic resonance image in the preferred mammal body, comprise that the compositions with effective dose is administered in the gastrointestinal tract of said health, before the administration, described human body or the fasting of non-human animal's body elder generation at least 6 hours, preferably at least 10 hours, more preferably at least 12 hours, said compositions comprises (a) and contains first kind of radiography contrast medium that physiology can tolerate manganese compound or its salt, and wherein manganese compound is substantially devoid of and comprises a large amount of Mn 2+-sting and close unitary hydrophilic polymer, (b) second kind of radiography contrast medium, preferably can in gastrointestinal tract, produce the correlated radiography contrast medium of negativity, produce the image at said health radiography position, for example the image of intestinal, liver or whole abdominal part with first kind of radiography contrast medium.This method is convenient to produce a series of images at health institute radiography position, produces 3-dimensional image.
Radiography contrast medium compositions used according to the invention can contain other composition, Chang Yong pharmaceutical necessities for example, for example for example sterilized water, water/ethanol etc. of wetting agent, buffer agent, disintegrating agent, binding agent, filler, flavoring agent and liquid-carrier.
For oral administration, the pH value of compositions preferably in acid range, 2-7 for example, simultaneously, the picked-up promoter of containing itself can help to prepare the compositions with this pH value, also can use buffer agent or PH regulator.
The radiography contrast medium can be made conventional form of administration, for example tablet, capsule, powder, solution, dispersant, syrup, suppository etc.
Radiography contrast medium preferred dosage is according to many factors and changing, and for example route of administration, age, experimenter's body weight and kind are and if contain used concrete picked-up promoter.Usually, the dosage of manganese can be the standard daily dose recommended 2-400 doubly, 5-500 μ mol/kg body weight for example, preferred 5-150 μ mol/kg body weight, more preferably 10-100 μ mol/kg body weight simultaneously, is absorbed promoter if use, its dosage can be 5 μ mol-1mmol/kg body weight, preferred 25 μ mol-0.5mmol/kg body weight.
Further describe embodiment of the present invention below by diagram and with reference to accompanying drawing.
Fig. 1 shows and uses MnCl 2(100 μ mol/kg) to fasting rat and fasting rat (18 hours) oral administration not after 2 hours, to horizontal T in the rat liver 1The influence of spin echo image (TR/TE=57/13ms) signal intensity of-weighting.
Fig. 2 shows and uses MnCl 2(25 μ mol/kg) to fasting healthy volunteer oral administration not after 4 hours, to horizontal T among the human liver 1The influence of the gtadient echo image of weighting (TR/TE-52.5/4.8ms, flip angle=80 °) signal intensity.
Fig. 3 shows and uses MnCl 2(25 μ mol/kg) to healthy volunteer's oral administration of fasting (12 hours) after 4 hours, to horizontal T among the human liver 1The influence of the gtadient echo image of-weighting (TR/TE-52.5/4.8ms, flip angle=80 °) signal intensity.
Fig. 4 shows and uses MnCl 2(100 μ mol/kg)+Abdoscan (80 μ mol Fe/kg) is to fasting rat (24 hours) oral administration after 2.5 hours, to horizontal T 1The influence of spin echo image (TR/TE=120/12ms) signal intensity of-weighting.Colon wall signal of video signal intensity significantly strengthens.
Fig. 5 shows MnCl 2(200 μ mol/kg) and alanine (400 μ mol/kg) together and not with alanine together to behind fasting rat (12 hours) oral administration, to horizontal T in the rat liver 1The influence of spin echo image (TR/TE=57/13ms) signal intensity of-weighting.Signal strengthens makes correlated signal in order to corresponding tester: the percent that noise ratio increases is represented.

Claims (26)

1. physiology can tolerate manganese compound or the purposes of its salt in the MRI radiography contrast medium compositions of making the enteral administration, and wherein said manganese compound or its salt are substantially devoid of and comprise a large amount of Mn 2+-to sting and close unitary hydrophilic polymer, described radiography contrast medium compositions is used in the angiographic method of a kind of people or non-human animal's body, before the administration of compositions enteral, human body or the fasting of non-human animal's body elder generation at least 6 hours.
2. physiology can tolerate manganese compound or the purposes of its salt in the MRI radiography contrast medium compositions of making rectally, and wherein said manganese compound or its salt are substantially devoid of and comprise a large amount of Mn 2+-to sting and close unitary hydrophilic polymer, described radiography contrast medium compositions is used in the angiographic method of a kind of human body or non-human animal's body, is substantially devoid of during the inherent imaging of the gastrointestinal tract of wherein said people or non-human animal's body to comprise a large amount of Mn 2+-sting and close unitary hydrophilic polymer composition.
3. according to the purposes of claim 2, wherein said people or non-human animal first fasting at least 6 hours before described compositions administration.
4. according to the purposes of claim 1 or 2, wherein said people or non-human animal first fasting at least 10 hours before described compositions administration.
5. according to the purposes of the arbitrary claim of claim 1-4, the concentration of manganese is greater than 10mM in the wherein said radiography contrast medium compositions.
6. according to the purposes of the arbitrary claim of claim 1-4, the concentration of manganese is 0.1mM-10mM in the wherein said radiography contrast medium compositions.
7. according to the purposes of arbitrary pro-claim, wherein said manganese compound is chela and the thing or the salt of bivalent manganese.
8. according to the purposes of arbitrary pro-claim, wherein said manganese compound is manganese chloride, Manganese ascorbate or kojic acid manganese.
9. according to the purposes of arbitrary pro-claim, wherein said radiography contrast medium compositions is individually dosed, is at another kind of radiography contrast medium and/or before promoting manganese to pass the picked-up promoter administration of gastrointestinal tract film transportation, during the administration or administration after the administration.
10. according to the purposes of claim 9, wherein said radiography contrast medium compositions and said another kind of radiography contrast medium and/or picked-up promoter are with the form administration of compound preparation.
11. physiology can tolerate manganese compound or its salt and another kind of radiography contrast medium and/or the purposes of picked-up promoter in making MRI radiography contrast medium compositions, wherein said manganese compound or its salt are substantially devoid of and comprise a large amount of Mn 2+-sting and close unitary hydrophilic polymer, described radiography contrast medium compositions is used in the angiographic method of a kind of human body or non-human animal's body, compositions while, independent or successive administration, before the administration of described radiography contrast medium compositions enteral, human body or the fasting of non-human animal's body elder generation at least 6 hours.
12. according to the purposes of the arbitrary claim of claim 9-11, wherein said picked-up promoter comprises that the physiology with an Alpha-hydroxy ketone group can tolerate the reproducibility chemical compound, has α-and/or beta-hydroxy or amino acid, vitamin D or its mixture.
13. according to the purposes of the arbitrary claim of claim 9-12, wherein said picked-up promoter is selected from ascorbic acid, kojic acid, gluconic acid and salicylic acid.
14. according to the purposes of the arbitrary claim of claim 9-12, wherein said picked-up promoter comprises α-or beta-amino acids.
15. according to the purposes of claim 14, wherein said aminoacid is selected from alanine, glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine.
16. according to the purposes of the arbitrary claim of claim 9-15, wherein manganese is 1 with the mol ratio of picked-up promoter: 0.2-1: 50.
17. according to the purposes of the arbitrary claim of claim 10-15, wherein said picked-up promoter exists with the form of the gegenion of manganese ion whole or in part.
18. according to the purposes of the arbitrary claim of claim 9-17, wherein said another kind of radiography contrast medium has negativity radiography effect.
19. according to the purposes of the arbitrary claim of claim 9-18, wherein said another kind of radiography contrast medium is substantially devoid of and comprises a large amount of Mn 2+-sting and close unitary hydrophilic polymer.
20. according to the purposes of the arbitrary claim of claim 9-19, wherein said another kind of radiography contrast medium is selected from: (a) microgranule of ferromagnetism or superparamagnetic material;
(b) be attached to Gd or Dy ion on the polymeric matrices;
(c) gas, gas generate agent or are filled with the granule of gas; With
(d) insoluble barium compound.
21. according to the purposes of the arbitrary claim of pro-, wherein said angiographic method can produce a series of images in being less than 20 seconds interval.
22. according to the purposes of the arbitrary claim of pro-, wherein said angiographic method is spin echo maskaperture mask or gtadient echo maskaperture mask.
23. according to the purposes of the arbitrary claim of pro-, wherein said angiographic method can provide the image of stomach, intestinal, liver, bile duct or the gallbladder of said health.
24. according to the purposes of the arbitrary claim of claim 1-22, wherein said angiographic method can provide a series of images of the whole abdominal part of said health.
25. in people or non-human animal's body, produce the method for magnetic resonance image, comprise and physiology can be tolerated manganese compound or its salt is administered in the gastrointestinal tract of said health, produce the image at said health radiography position, wherein manganese compound is substantially devoid of and comprises a large amount of Mn 2+-sting and close unitary hydrophilic polymer, before the administration, described human body or the fasting of non-human animal's body elder generation at least 6 hours.
26. in people or non-human animal's body, produce the method for magnetic resonance image, comprise that the compositions with effective dose is administered in the gastrointestinal tract of said health, produce the image at said body imaging position, before the enteral administration, described human body or the fasting of non-human animal's body elder generation at least 6 hours, said compositions comprises (a) and comprises that physiology can tolerate first kind of radiography contrast medium of manganese compound or its salt, wherein is substantially devoid of to comprise a large amount of Mn 2+-sting and close unitary hydrophilic polymer and (b) second kind of radiography contrast medium.
CN 97180009 1996-09-23 1997-07-30 Method Pending CN1238698A (en)

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DK531488A (en) * 1987-09-25 1989-03-26 Salutar Inc NMR IMAGE CREATION WITH MN (II) COORDINATION RELATIONS
IT1252145B (en) * 1991-11-29 1995-06-05 Bracco Ind Chimica Spa METHOD AND FORMULATIONS SUITABLE FOR IMPROVING THE STUDY OF CABLES IN MEN
JP2911674B2 (en) * 1992-02-20 1999-06-23 明治乳業株式会社 Gastrointestinal imaging composition
GB9208908D0 (en) * 1992-04-24 1992-06-10 Nycomed As Contrast agents
WO1996005867A2 (en) * 1994-08-18 1996-02-29 Nycomed Imaging A/S Compositions
DK81095A (en) * 1995-07-11 1997-01-12 Henrik S Thomsen Oral MR contrast agent for liver and upper intestinal tract

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JP2001500870A (en) 2001-01-23
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AU3776697A (en) 1998-04-14
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