CA2265856A1 - Method - Google Patents

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 Mn2+- 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

W0 98/11921CA 02265856 1999-03-09PCTIGB97/02072MethndThe present invention relates to improvements inand relating to magnetic resonance imaging (MRI), inparticular to the use of manganese compounds in thepreparation of contrast media for imaging of theabdomen.MRI is now well established as a medical diagnostictool. The ability of the technique to generate highquality images and to differentiate between soft tissueswithout requiring the patient to be exposed to ionizingradiation has contributed to this success.Although MRI can be performed without using addedcontrast media, it has been found that substances whichaffect the nuclear spin reequilibration of the nuclei(hereinafter the "imaging nuclei" — generally waterprotons in body fluids and tissues) responsible for themagnetic resonance (MR) signals from which the imagesare generated may be used to enhance image contrast and,accordingly, in recent years, many such materials havebeen suggested as MRI contrast agents.The enhanced contrast obtained with the use ofcontrast agents enables particular organs or tissues tobe visualized more clearly by increasing or bydecreasing the signal level of the particular organ ortissue relative to that of its surroundings. Contrastagents raising the signal level of the target siterelative to that of its surroundings are termed"positive" contrast agents whilst those lowering thesignal level relative to surroundings are termed"negative" contrast agents.Development of MRI as a technique for imaging thegastrointestinal (g.i.) tract, or indeed the abdomen ingeneral, has been hindered by problems particular to theabdomen in which natural inter—tissue contrast isrelatively poor and by the absence of a particularlySUBSTITUTE SHEET (RULE 26)CA 02265856 1999-03-09W0 98/1 1921 PCT/GB97/02072effective contrast medium.The majority of materials now being proposed as MRIcontrast media achieve a contrast effect because theycontain paramagnetic, superparamagnetic or ferromagneticspecies.Paramagnetic contrast agents may be either positiveor negative MRI contrast agents. The effect ofparamagnetic substances on magnetic resonance signalintensities is dependent on many factors, the mostimportant of which are the concentration of theparamagnetic substance at the imaged site, the nature ofthe paramagnetic substance itself and the pulse sequenceand magnetic field strength used in the imaging routine.Generally, however, paramagnetic contrast agents arepositive MRI contrast agents at low concentrations wheretheir T1 lowering effect dominates and negative MRIcontrast agents at higher concentrations where their T2(or 13*) lowering effect is dominant.An example of a physiologically tolerableparamagnetic material known for use as an MRI contrastagent is manganese ion, which may conveniently be usedin the form of its salts or chelates. Howevermanganese, when administered intravenously as a contrastagent, may be teratogenic at clinical dosages.Administered intravenously, manganese is also known tointerfere with the normal functioning of the heart byreplacement of calcium in the calcium pump of the heart.In order to reduce the direct effect on the heart,oral administration of manganese has been proposed. Aresult of the vascularisation of the upper g.i. tract isthat orally administered material taken up into theblood from the gut passes to the liver before passing tothe heart. In the case of manganese, absorption by thehepatocytes in the liver prevents cardiotoxic levels ofmanganese reaching the heart. This hepatocyte uptake ofmanganese thus means that orally administered manganesecould be used as a liver imaging MR contrast agent.CA 02265856 1999-03-09W0 98/1 1921 PCT/GB97/02072- 3 _However, in early animal studies no diagnosticallyeffective uptake of orally administered MnCl2 through thegut wall was found when manganese was given inclinically relevant doses. Moreover, orallyadministered, manganese containing g.i. tract MRcontrast media, such as the manganese/hydrophilicpolymer composition Lumenhance, show no contrastenhancement other than in the content of the gut.It was therefore considered that to achieve uptakefrom the gut of diagnostically effective, i.e. contrasteffective, quantities of manganese, the use of materialswhich positively promote manganese uptake was requiredand WO—A—96/05867 proposed as a solution to this problemof inadequate uptake of manganese in the gut the use ofmanganese contrast agents in combination with one ormore uptake promoters capable of enhancing manganesetransport across the membranes of the g.i. tract.Examples of such uptake promoters include ascorbic andkojic acids.However, there still exists the need for improvedmethods of MR imaging using manganese contrast agents,in particular for imaging of the abdomen, e.g. the liverand the g.i. tract.We have now surprisingly found that diagnosticallyeffective levels of uptake of orally or rectallyadministered manganese may be achieved simply byensuring that no food or no hydrophilic polymercomponents containing a significant amount of a Mn“-chelating unit are simultaneously present in the gut,e.g. by administering manganese chloride following aperiod of fasting. By "significant amount" is meantthat the amount of Mn”- chelating unit is sufficientlyhigh so as to influence the uptake of manganese.Whilst not wishing to be bound by theoreticalconsiderations, it is believed that food present in thegut, and in particular constituents of food containinghydrophilic polymer components containing a significantCA 02265856 1999-03-09WO 98/1 1921 PCT/GB97/02072_ 4 _amount of a Mn”— chelating unit, form tight complexeswith the manganese ions thereby hindering manganesetransport across the membranes of the g.i. tract.Thus viewed from one aspect the invention providesthe use of a physiologically tolerable manganesecompound or a salt thereof, substantially free fromhydrophilic polymer components containing a significantamount of a Mn”- chelating unit, in the manufacture ofan enterally, e.g. orally or rectally, administrable MRIcontrast medium composition for use in a method ofimaging of a human or non—human animal body which hasfasted for a period of at least 6, preferably at least10, more preferably at least 12 hours before enteraladministration of said composition.By fasting it is meant that no solid food which maycontain hydrophilic polymer components containing a’significant amount of a Mn”— chelating unit, inparticular soluble or fibrous hydrophilic polymers, hasbeen consumed within the stated period. Water or sugarcontaining fluids may be taken during the fastingperiod.In a particularly preferred embodiment of theinvention, the manganese contrast agent is administeredsubstantially in the absence of any uptake promoter,e.g. ascorbic acid.In an alternative embodiment the invention providesa method of obtaining enhanced images of the liver andthe lower gut by means of rectal administration of thecontrast medium. Due to the special vascularisation ofthe lower gut, a proportion of the rectally administeredmanganese passes directly to the heart followingabsorption, without first passing through the liver. Wehave, however, surprisingly found that effective uptakeof manganese in the lower gut can be achieved using muchlower doses of rectally administered manganese,resulting in particularly enhanced images of the liverand lower gut. This is of particular value in detectingCA 02265856 1999-03-09W0 98/ 1 1921 » PCT/GB97/020725-tumors in the lower gut, e.g. in the diagnosis ofcolorectal cancer.Viewed from a further aspect the invention thusprovides the use of a physiologically tolerablemanganese compound or a salt thereof, substantially freefrom hydrophilic polymer components containing asignificant amount of a Mn“— chelating unit, in themanufacture of a rectally administrable MRI contrastmedium composition for use in a method of imaging of ahuman or non-human animal body wherein the g.i. tract ofsaid body is substantially free from hydrophilic polymercomponents containing a significant amount of a Mn“-chelating unit at the time of imaging. Conveniently,the contrast medium composition is administered to ahuman or non-human animal body which has fasted for aperiod of at least 6, preferably at least 10, morepreferably at least 12 hours"Maximum uptake of rectally administered manganesemay, however, be achieved by prior irrigation of thecolon, thereby ensuring that this is substantially freefrom any hydrophilic polymer components containing asignificant amount of a Mn”— chelating unit. As soon asthe gut is cleared of any undesirable hydrophilicpolymer components, manganese uptake in the gut occursand images can be produced.Rectal administration may be via rectally insertedtubes which enable administration of the contrast mediumto a selected region of the gut.Conveniently, the manganese compound may be presentin the contrast medium composition at a concentration ofat least 0.3mM or, alternatively, may be present in adosage unit form containing at least 300pmol manganese.The manganese compound, which for oraladministration is preferably soluble in gastrointestinalfluid, may for example be a chelate or a salt, or may bea mixture of different salts and/or chelates.Particularly preferred are metal chelates and salts inCA 02265856 1999-03-09W0 98/1 1921 PCT/GB97/02072_ 5 -which the manganese is present as Mn(II) rather thanMn(III) since the former has a higher magnetic momentand thus is more effective as an MR contrast agent.Examples of manganese compounds particularlysuitable for use in accordance with the inventioninclude manganese chloride, ascorbate and kojate.The manganese compounds may conveniently be used incombination with one or more uptake promoters, such asthose described in W0-A—96/05867. In this regard, thecontrast media compositions may be administered as acombined preparation with the uptake promoter or,alternatively, may be administered separately, prior to,during or subsequent to administration of the uptakepromoter. Alternatively, the manganese compound isadministered substantially free from such uptakepromoter.Suitable uptake promoters include reducingcompounds containing an d-hydroxy ketone group(~CH(OH)—CO—), acids containing d— and/or B—hydroxy oramino groups,*vitamin D and mixtures thereof. Thereducing nature of the uptake promoter is importantsince normal uptake of manganese by the gut tends tofavour Mn(II) rather than Mn(III).As used herein, the expression "acids containing d—and/or B—hydroxy or amino groups" is intended to includearomatic acids containing ortho—hydroxy or ortho-aminogroups.Preferred uptake promoters include those in whichthe reducing compound further contains an oxygen atom ina heterocyclic ring structure.Particularly preferred as an uptake promoter isascorbic acid which has been found to increase theuptake of manganese in the g.i. tract about 5-foldcompared with oral administration of MnCl2 alone.Moreover, ascorbic acid (vitamin C) is cheap, readilyavailable and particularly well tolerated by the body.When administered orally, it also serves to mask theCA 02265856 1999-03-09W0 98/1 1921 PCTlGB97l02072_ 7 -metallic taste of the manganese, thus improving thetaste of the contrast medium.Also preferred as an uptake promoter is kojic acid.Examples of acids which have been found to beparticularly effective as uptake promoters includecarboxylic acids, e.g. gluconic and salicylic acid.d— and B—amino acids have also been found to be usefulas uptake promoters, in particular d—amino acids, e.g.alanine, glycine, valine, glutamine, aspartic acid,glutamic acid, lysine, arginine, cysteine andmethionine, especially arginine, lysine and asparticacid.Conveniently, the molar ratio of manganese touptake promoter is from 1:O.2 to 1:50, e.g. 1:1 to 1:20,particularly 1:1 to 1:10, more preferably 1:1 to 1:8,yet more preferably 1:1 to 1:6, especially 1:2 to 1:6,particularly preferably about 1:5.Alternatively, the molar ratio of manganese touptake promoter may be in the range of from 1:1.S to1:5, e.g. 1:1.S to 1:4, particularly 1:2 to 1:4,especially 1:2 to 1:3, particularly preferably about1:2.The uptake promoter may if desired be present inwhole or in part as the counterion to the manganeseions. Thus in one embodiment the manganese compound foruse in accordance with the invention comprises amanganese salt of a reducing compound containing an a-hydroxy ketone group, or a manganese salt of an acidcontaining u- and/or B- hydroxy or amino groups, e.g.manganese (II) ascorbate or manganese salicylate.As mentioned above, paramagnetic materials such asmanganese ions may act as either positive or negativeMRI contrast agents depending upon a number of factors,including the concentration of the ions at the imagingsite and the magnetic field strength used in the imagingprocedure. Depending upon the resulting manganese ionconcentration within the g.i. tract, this may be such asCA 02265856 1999-03-09W0 98/ l 1921 PCT/GB97/02072_ 8 _to create a signal suppressing or enhancing effectthere. In this way a "double contrast effect" andmargin definition can thus be achieved with varyingconcentrations of manganese.Whilst a broad range of manganese concentrations isdeemed to fall within the scope of the invention, therewill generally be two preferred concentration ranges -one enabling strong negative contrast to be obtainedbetween the stomach and the surrounding muscle tissueand the other providing strong positive contrast. Fornegative contrast the concentration of manganese isconveniently greater than l0mM, preferably in the rangeof from l0mM to 50mM. For positive contrast the _manganese concentration is conveniently in the range offrom 0.1mM to lOmM, preferably from lmM to 6mM.When using the contrast media to obtain a doublecontrast effect, in order to avoid image artefactsresulting from pockets of the gut being contrast agentfree, it is desirable to incorporate in the contrastmedia a viscosity enhancing agent and/or an osmoactiveagent, these being other than a hydrophilic polymercomponent containing a significant amount of a Mn“-chelating unit. Examples of suitable viscosityenhancers and osmoactive agents are described in WO—A—91/01147 and WO—A—9l/01148 .The contrast media compositions may also be used incombination with a second contrast agent, preferably onewhich is retained within the gut and there exhibits anegative contrast effect. This results in a doublecontrast effect enabling visualisation and margindefinition of the abdomen to be particularly enhanced.In this regard, the contrast media may be administeredas a combined preparation with a second contrast agent.Alternatively, the second contrast agent may beadministered separately, prior to, during or subsequentto administration of the manganese—containing contrastmedium.CA 02265856 1999-03-09W0 98/1 1921 PCT/GB97/02072- 9 _Viewed from a further aspect the invention thusprovides the use of a physiologically tolerablemanganese compound or a salt thereof, substantially freefrom hydrophilic polymer components containing asignificant amount of a Mn“— chelating unit, togetherwith a second contrast agent having a negative contrasteffect in the gut, in the manufacture of MRI contrastmedium compositions for simultaneous, separate orsequential administration in a method of imaging of ahuman or non—human animal body which has fasted for aperiod of at least 6, preferably at least 10, morepreferably at least 12 hours before enteraladministration of said compositions.Depending upon the concentration of manganesepresent, the manganese—containing contrast agent mayfunction either as a positive or a negative contrastagent. In general, at the concentrations contemplatedfor use in accordance with the"invention the manganese-containing contrast agent will function as a positivecontrast agent. The second contrast agent is thereforeconveniently a negative contrast agent and may be anynegative MRI contrast agent suitable for enteraladministration.Conveniently, the second contrast agent issubstantially free from hydrophilic polymers containinga significant amount of a Mn”— chelating unit.’Examples of negative MRI contrast agents for use inaccordance with the method of the invention includeknown ferromagnetic and superparamagnetic species, e.g.AMI 227, SINEREM from Advanced Magnetics, and forexample magnetic iron oxide particles either free orenclosed within or bound to a non-magnetic matrixmaterial such as the magnetic polymer particlesavailable under the trade names LUMIREM (Guerbet SA) andABDOSCAN (Nycomed Imaging AS).Further examples of a second contrast agent for usein accordance with the method of the invention includeCA 02265856 1999-03-09W0 98/11921 PCT/GB97/02072_ 1 0 _Gd and Dy ions bound to a polymeric matrix, for examplethe materials available under the trade name GADOLITE(Gadolinium alumina silicate oral suspension), availablefrom Pharmacyclics. Yet further examples include knownsusceptibility agents such as insoluble bariumcompounds, e.g. barium sulphate, and other agentscommonly used in barium meals or barium enemas in X—rayinvestigations of the gut.Since the manganese is also present in the g.i.tract, the quantity of the second contrast agentnecessary to achieve negative contrast within the gutmay be significantly lower, e.g. 1/10 to 1/2 thequantity required in the absence of the manganese.When using the manganese compositions in accordancewith the invention to achieve a double contrast effect,it is particularly preferable to incorporate into thecontrast medium a Viscosity enhancing agent, other thana hydrophilic polymer component containing a significantamount of a Mn“— chelating unit, which attains its fullviscosity enhancing effect only after administration ofthe contrast medium. The contrast medium is thus ableto be ingested in a relatively tolerable form while yetdeveloping the desired viscosity at or during passagetowards the site which is to be imaged.Other examples of negative contrast agents suitablefor use in accordance with the invention include gases,gas generating agents or gas filled particles. Thus,the second contrast agent may comprise a gas generatingagent capable of releasing a gas, such as CO2 or N”following oral administration. Preferred gas generatingagents are those capable of releasing CO2 or N; onContact with the gastric juices in the stomach.Alternatively, if delayed release of the gas isdesirable, this can be achieved by providing the gasgenerating agent with a coating which does not dissolveon contact with the gastric juices. Examples ofsuitable gas generating agents for use in accordanceCA 02265856 1999-03-09W0 98/11921 — PCT/GB97/02072- ll —with the invention include MHCO3, NaQCO3 and NaHCO3.In a preferred embodiment of the invention, rectaladministration of the contrast medium may be combinedwith insufflation of the lower-g.i. tract to obtain aparticularly enhanced double contrast effect.Insufflation may conveniently be achieved by blowing agas, such as air, preferably CO2 or N2, into the lowercolon either simultaneously or subsequent toadministration of the manganese contrast agent. In thisway, the bulk of the lower colon is filled with gas andthe manganese contrast agent coats the walls of the gut.In the resulting MR images, the bulk of the colon isblackened out and the gut walls and liver arehighlighted.One of the problems encountered in imaging of theabdomen, in particular the g.i. tract, is that the MRsignal intensity has a tendency to vary due to physicalmovements in the region being imaged. This problem canto some extent be overcome by the use of fast imagingprocedures. Techniques capable of generating imageswith time intervals of less than 20 seconds (thusenabling imaging during one single "breath hold") arepreferred for use in accordance with the method of theinvention. Particularly suitable techniques includespin echo procedures (TR = 80—l50ms, TE = 10-14ms) andgradient echo procedures (TR z 50ms, TE = 4ms, flipangle = 80—90°). The gradient echo sequence shouldpreferably be spoiled.The contrast agent compositions for use in theinvention are particularly suited to use, if requiredafter dispersion in aqueous media, for imaging of theabdomen, in particular the stomach, intestine, liver,bile duct and gall bladder. For such a purpose thecontrast media may be administered into thegastrointestinal tract orally, rectally or via a stomachtube. The method of the invention is capable ofgenerating high quality 3D images of the abdomen, inCA 02265856 1999-03-09W0 98/1 1921 PCT/GB97/02072_ 1 2 _particular of the liver. The method is also ofparticular value in providing clear images showing thestructure of the gut wall, thus enabling detection ofany abnormalities in the gut wall.Viewed from another aspect the invention thusprovides a method of generating a magnetic resonanceimage of a human or non—human, preferably mamalian,animal body, which method comprises administering intothe gastrointestinal tract of a said body which hasfasted for at least 6, preferably at least 10, morepreferably at least 12 hours prior to enteraladministration, a physiologically tolerable manganesecompound or a salt thereof, substantially free fromhydrophilic polymer components containing a significantamount of a Mn“— chelating unit, and generating an imageof a part of said body.Viewed from a yet further aspect the inventionprovides a method of generating a magnetic resonanceimage of a human or non—human, preferably mammalian,animal body, which method comprises administering intothe gastrointestinal tract of a said body which hasfasted for at least 6, preferably at least 10, morepreferably at least 12 hours prior to enteraladministration, an effective amount of a compositioncomprising (a) a first contrast agent comprising aphysiologically tolerable manganese compound or a saltthereof, substantially free from hydrophilic polymercomponents containing a significant amount of a Mn”-chelating unit, together with (b) a second contrastagent, preferably one capable with said first agent ofachieving negative contrast in the gastrointestinaltract, and generating an image of a part of said body,e.g. the gut, liver or the whole of the abdomen. Such amethod may conveniently be used to generate a series ofimages through the part of the body being imaged,resulting in the production of 3D images.The contrast medium compositions for use inCA 02265856 1999-03-09W0 98/11921 PCT/GB97/02072_ 13 -accordance with the invention may include othercomponents, for example conventional pharmaceuticalformulation aids such as wetting agents, buffers,disintegrants, binders, fillers, flavouring agents andliquid carrier media such as sterile water,water/ethanol etc.For oral administration, the pH of the compositionis preferably in the acid range, eg. 2 to 7 and whileany uptake promoter present may itself serve to yield acomposition with this pH, buffers or pH adjusting agentsmay be used. .The contrast media may be formulated inconventional pharmaceutical administration forms, such Vas tablets, capsules, powders, solutions, dispersions,syrups, suppositories etc.The preferred dosage of the contrast media willvary according to a number of factors, such as theadministration route, the age, weight and species of thesubject and, if present, the particular uptake promoterused. Conveniently, the dosage of manganese may be inthe range of from 2-400 times the normal recommendeddaily dose of manganese, e.g. from 5 to 500 pmol/kgbodyweight, preferably from 5 to 150 pmol/kg bodyweight,more preferably from 10 to 100 pmol/kg bodyweight, whilethe dosage of the uptake promoter, if present, may be inthe range of from 5 umol to l mmol/kg bodyweight,preferably from 25 pmol to 0.5 mmol/kg bodyweight.Embodiments of the invention will now be furtherdescribed by way of illustration and with reference tothe accompanying figures, in which:Figure 1 illustrates the effect of orallyadministered MnCl2 (100 pmol/kg) on signal intensity oftransversal T3—weighted.spin—echo images (TR/TE = 57/13ms) in rat liver 2 hours after administration in non-fasted and fasted (18 hours) rats.Figure 2 illustrates the effect of orallyadministered MnCl3 (25 pmol/kg) on signal intensity of aCA 02265856 1999-03-09W0 98/1 1921 PCT/GB97/02072_ 14 -transversal T3—weighted gradient—echo image (TR/TE =52.5/4.8 ms, flip angle = 80°) in human liver 4 hoursafter administration in a non—fasted healthy volunteer.Figure 3 illustrates the effect of orallyadministered MnCl2 (25 pmol/kg) on signal intensity of atransversal T3—weighted gradient—echo image (TR/TE =52.5/4.8 ms, flip angle = 80°) in human liver 4 hoursafter administration in a fasted (12 hours) healthyvolunteer.Figure 4 illustrates the effect of rectallyadministered MnCl2 (100 pmol/kg) + Abdoscanf (80 pmolFe/kg) on signal intensity of coronal T3-weighted spin-echo images (TR/TE = 120/12 ms) 2% hours afteradministration in fasted (24 hours) rats. The strongenhancement of the signal intensity of the colon wall isto be noted.Figure 5 illustrates the effect of orallyadministered MnCl2 (200 pmol/kg), both with and withoutco—administration of alanine (400 pmol/kg), on signalintensity of T3—weighted spin—echo images (TR/TE = 57/13ms) in rat liver following administration in fasted (12hours) rats. Signal enhancement is expressed as a %increase of signal:noise ratio compared to acorresponding control.

Claims (26)

Claims:

1. 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 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 hours before enteral administration of said composition.

2. 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 a rectally administrable MRI contrast medium composition for use in a method of imaging of a human or non-human animal body wherein the gastrointestinal tract of said body is substantially free from hydrophilic polymer components containing a significant amount of a Mn2+ - chelating unit at the time of imaging.

3. Use as claimed in claim 2 wherein said body has fasted for a period of at least 6 hours prior to administration of said composition.

4. Use as claimed in claim 1 or claim 2 wherein said body has fasted for a period of at least 10 hours prior to administration of said composition.

5. Use as claimed in any one of claims 1 to 4 wherein said contrast medium composition has a manganese concentration greater than 10mM.

6. Use as claimed in any one of claims 1 to 4 wherein said contrast medium composition has a manganese concentration of from 0.1mM to 10mM.

7. Use as claimed in any preceding claim wherein said manganese compound is a chelate or a salt in which the manganese is present as Mn(II).

8. Use as claimed in any preceding claim wherein said manganese compound is manganese chloride, manganese ascorbate or manganese kojate.

9. Use as claimed in any preceding claim wherein said contrast medium composition is administered separately, prior to, during or subsequent to administration of a second contrast agent and/or an uptake promoter capable of enhancing manganese transport across the membranes of the gastrointestinal tract.

10. Use as claimed in claim 9 wherein said contrast medium composition is administered as a combined preparation with said second contrast agent and/or said uptake promoter.

11. 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, together with a second contrast agent and/or an uptake promoter, in the manufacture of MRI contrast medium compositions for simultaneous, separate or sequential administration in a method of imaging of a human or non-human animal body which has fasted for a period of at least 6 hours before enteral administration of said compositions.

12. Use as claimed in any one of claims 9 to 11 wherein said uptake promoter comprises a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group, a physiologically tolerable acid containing .alpha.- and/or .beta.-hydroxy or amino groups, vitamin D, or a mixture thereof.

13. Use as claimed in any one of claims 9 to 12 wherein said uptake promoter is selected from ascorbic acid, kojic acid, gluconic acid and salicylic acid.

14. Use as claimed in any one of claims 9 to 12 wherein said uptake promoter comprises an .alpha.- or .beta.-amino acid.

15. Use as claimed in claim 14 wherein said acid is selected from alanine, glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine.

16. Use as claimed in any one of claims 9 to 15 wherein the molar ratio of manganese to uptake promoter is from 1:0.2 to 1:50.

17. Use as claimed in any one of claims 10 to 15 wherein said uptake promoter is present in whole or in part as the counterion to the manganese ions.

18. Use as claimed in any one of claims 9 to 17 wherein said second contrast agent has a negative contrast effect.

19. Use as claimed in any one of claims 9 to 18 wherein said second contrast agent is substantially free from hydrophilic polymers containing a significant amount of a Mn 2+ - chelating unit.

20. Use as claimed in any one of claims 9 to 19 wherein said second contrast agent is selected from:
(a) a particulate ferromagnetic or superparamagnetic material;
(b) Gd or Dy ions bound to a polymeric matrix;

(c) a gas, a gas generating agent or gas filled particles; and (d) insoluble barium compounds.

21. Use as claimed in any preceding claim wherein said method of imaging is capable of generating a series of images with time intervals of less than 20 seconds.

22. Use as claimed in any preceding claim wherein said method of imaging is a spin echo or gradient echo imaging procedure.

23. Use as claimed in any preceding claim wherein said method of imaging provides an image of the stomach, intestine, liver, bile duct or gall bladder of said body.

24. Use as claimed in any one of claims 1 to 22 wherein said method of imaging provides a series of images of the whole abdomen of said body.

25. A method of generating a magnetic resonance image of a human or non-human animal body, which method comprises administering into the gastrointestinal tract of a said body which has fasted for at least 6 hours prior to enteral administration, 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, and generating an image of a part of said body.

26. A method of generating a magnetic resonance image of a human or non-human animal body, which method comprises administering into the gastrointestinal tract of a said body which has fasted for at least 6 hours prior to enteral administration, an effective amount of a composition comprising (a) a first contrast agent comprising 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, together with (b) a second contrast agent, and generating an image of a part of said body,