WO2010099804A1

WO2010099804A1 - Magnetic resonance imaging of the liver

Info

Publication number: WO2010099804A1
Application number: PCT/EP2009/001567
Authority: WO
Inventors: Nils-Olof Johansson
Original assignee: Cmc Contrast Ab
Priority date: 2009-03-05
Filing date: 2009-03-05
Publication date: 2010-09-10

Abstract

Method for examination of the liver of a human patient, comprising the following sequential steps: a) providing a contrast agent comprising a physiologically acceptable non-chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D; b) administering the contrast agent orally or gastrically to the patient; and c) subjecting the patient to magnetic resonance imaging (MRI) of the liver about 1-6 hours after administration of the contrast agent. Contrast agent as above for use in examination of the liver of a human patient by administration to the patient about 1-6 hours before subjecting the patient to MRI. Use of a physiologically acceptable non-chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D for the manufacture of a contrast agent for examination of the liver of a human patient by administration to the patient about 1-6 hours before subjecting the patient to MRI.

Description

MAGNETIC RESONANCE IMAGING OF THE LIVER

Technical field

The present invention relates to a method for examination of the liver of a human patient, involving administration of a manganese (II) based contrast agent to the patient and subjecting the patient to magnetic resonance imaging. The present invention further relates to a manganese (II) based contrast agent for use in examination of the liver of a human patient by magnetic resonance imaging; and to the use of, i.a., a manganese (II) compound for the manufacture of a contrast agent for examination of the liver of a human patient by magnetic resonance imaging.

Background art

Magnetic resonance imaging (MRI) of the liver may be improved by the use of a manganese based contrast medium. Manganese, however, when administered intravenously as a contrast agent, may be teratogenic at clinical dosages. Administered intravenously, manganese is also known to interfere with the normal functioning of the heart by replacement of calcium in the calcium pump of the heart. In order to reduce the direct effect on the heart, oral administration has been proposed. This ensures that, according to the so-called first pass effect, manganese carried from the small intestine to the liver is returned from the liver via the bile to the small intestine without reaching systemic circulation.

WO 96/005867 discloses a contrast medium composition comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0.3 mM or being in a dosage unit form containing at least 300 μmol manganese, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an α-hydroxy ketone group, a physiologically tolerable acid containing α- and/or β-hydroxy or amino groups, or a salt thereof, and/or vitamin D. It is disclosed that such compositions are particularly suitable for imaging of the liver. WO 97/02842 discloses a composition for use as a contrast medium being particularly suitable for imaging of the stomach, liver, bile duct and gall bladder, said composition comprising as an active ingredient a physiologically acceptable manganese compound and an uptake promoter, wherein the uptake promoter comprises a physiologically acceptable reducing compound containing a physiologically acceptable amino acid or a salt thereof, and/or vitamin D.

WO 98/11922 discloses the use of a physiologically tolerable manganese compound or a salt thereof, in combination with a second contrast agent, preferably one which is retained within the gut and there exhibits a negative contrast effect, in the manufacture of an enterally, e.g. orally or rectally, administrable MRI contrast medium composition for use in a method of functional imaging of the gastrointestinal tract. Imaging of the liver is also disclosed. WO 2005/058375 discloses the use of a physiologically acceptable manganese (II) compound and an uptake promoter in the form of one or more amino acids for the manufacture of an MRI contrast composition for oral administration and MRI examination of the liver, in a ratio of Mn to promoter higher than that at which coordination compounds between Mn and promoter are formed to a substantial degree.

An MRI contrast medium for intravenous use based on mangafodipir (a chelate containing the metal manganese and the ligand fodipir, i.e., dipyridoxyl diphosphate) is known to provide near maximal enhancement of the normal liver parenchyma 15-20 minutes from the start of administration and lasting for approximately 4 hours. (Annex I₁ Summary of product characteristics, product information for Teslascan as available from the European Medicines Agency)

Efficient utilization of hospital resources calls for a great flexibility in timing as regards administration of the contrast medium and subsequent examination by MRI. Furthermore, recently developed treatments of focal liver lesions, such as radio frequency ablation, a minimally invasive technique, requires follow-up by imaging of the liver throughout treatment sessions lasting for several hours. Summary of the invention

An object of the present invention is to allow MRI of the liver to be performed during a wider time window after administration of the MRI contrast medium than was previously possible. Another object of the present invention is to allow MRI of the liver at a later occasion after administration of the MRI contrast medium than was previously possible.

It is a further object of the present invention to fulfil such timing aspects of contrast medium administration and MRI scanning while employing a safe mode of administration of a contrast medium providing a significant and homogeneous increase in MRI signal intensity of the liver.

It has surprisingly been found that the above-mentioned objects as well as further objects, which will become apparent to a skilled person after studying the description below, are achieved, in a first aspect, by a method for examination of the liver of a human patient, comprising the following sequential steps: a) providing a contrast agent comprising a physiologically acceptable non- chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D; b) administering the contrast agent orally or gastrically to the patient; and c) subjecting the patient to magnetic resonance imaging of the liver about

1-6 hours after administration of the contrast agent.

In a second aspect, the objects are achieved by a contrast agent comprising a physiologically acceptable non-chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D for use, in examination of the liver of a human patient, by oral or gastrical administration to the patient about 1-6 hours before subjecting the patient to magnetic resonance imaging of the liver.

In a third aspect, the objects are achieved by use of a physiologically acceptable non-chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D for the manufacture of a contrast agent for examination of the liver of a human patient by oral or gastrical administration to the patient about 1-6 hours before subjecting the patient to magnetic resonance imaging of the liver.

Paramagnetic materials, such as manganese ions, may act as either positive or negative MRI contrast agents depending upon a number of factors, including the concentration of the ions at the imaging site and the magnetic field-strength used in the imaging procedure. At the concentrations of manganese contemplated for use in the contrast agents of the invention, the manganese-containing contrast medium will in general function as a positive contrast medium. Presence in the contrast agent of a physiologically acceptable amino acid and a vitamin D promotes the uptake of the manganese (II) compound over the intestinal wall for passage to the liver. Compounds in which the manganese is present as Mn (II) rather than Mn (III) have been selected since the former has a better adsorption profile and is thus more efficient as an MRI contrast agent for imaging of the liver. Adsorption of chelated manganese compounds over the intestinal wall is limited, rendering non-chelated manganese (II) compounds suitable in connection with the present invention.

The composition may be administered into the gastrointestinal tract orally or gastrically, such as via a gastric tube. Thus, it has unexpectedly been found that already one hour after administration of the contrast agent, a satisfactory MRI signal intensity of the liver parenchyma relative to fat is achieved. Also unexpectedly, a satisfactory signal intensity remains up to six hours after administration of the contrast agent. The patient may be subjected to magnetic resonance imaging of the liver about 2-6 hours, preferably about 3-6 hours or about 3.5-6 hours, and more preferably about 4-6 hours or about 4.5-6 hours, after administration of the contrast agent. In other words, administration of the contrast agent may occur about 2-6 hours, preferably about 3-6 hours or about 3.5-6 hours, and more preferably about 4-6 hours or about 4.5-6 hours before subjecting the patient to magnetic resonance imaging of the liver. A significant change and increase in the MRI signal intensity starts after about two hours and remains substantially stable up to about six hours after administration of the contrast agent. A maximal MRI signal intensity may be reached about three hours after administration. It would be interesting to investigate whether the signal intensity will remain stable for even longer periods, such as eight or ten hours after administration of the contrast agent. The contrast agent may be administered orally. Thus, a patient can administer the contrast agent himself prior to MRI scanning. Since he can take the oral contrast agent himself without need for medical assistance, he is not obliged to arrive at the hospital several hours before being scanned. The preferred dosage of the contrast agent according to the present invention will vary according to a number of factors, such as the age and weight of the patient. Thus, the contrast agent may be administered in a dose providing about 1-10 mmol manganese (II), preferably about 2-5 mmol manganese (II), and more preferably about 2-4 mmol manganese (II), to the patient. Conveniently, the contrast agent may be administered in a dose providing about 25-150 μmol manganese (ll)/kg body weight, preferably about 50-125 μmol manganese (ll)/kg body weight, and more preferably about 50-100 μmol manganese (ll)/kg body weight, to the patient.

The uptake of manganese (II) in the liver, and thus the MRI signal intensity will vary according to the composition of the contrast agent as regards the presence of the uptake promoters, amino acid and vitamin D. Thus, in the contrast agent the molar ratio of manganese (II) to amino acid may be about 1 :1 to 1 :3, preferably about 1 :1 to 1 :2, and more preferably about 1 :1.2 to 1 :1.6. Also, in the contrast agent the ratio of vitamin D to manganese (II) may be about 50-1000 IU vitamin D/mmol manganese (II), preferably about 100-500 IU vitamin D/mmol manganese (II), and more preferably about 150-250 IU vitamin D/mmol manganese (II).

The manganese (II) compound may be a water soluble manganese (II) salt. Examples of manganese (II) compounds preferred for use in accordance with the invention include pharmaceutically acceptable salts, e.g. manganese chloride, manganese ascorbate, manganese kojate, manganese salicylate, and manganese gluconate. It is preferred that the physiologically acceptable non-chelate water soluble manganese (II) salt is MnC^. The contrast agent may comprise a mixture of different manganese (M) salts. Amino acids which are effective as uptake promoters in a contrast agent as used in the invention include all the native amino acids. Accordingly, the physiologically acceptable amino acid may be selected from the group consisting of alanine, valine, leucine, tryptophan, methionine, isoleucine, proline, phenylalanine, serine, glycine, threonine, cysteine, asparagine, glutamine, tyrosine, aspartic acid, glutamic acid, arginine, lycine and histidine. The physiologically acceptable amino acid may preferably be selected from neutral amino acids including asparagines and aspartic acid. Particularly preferred amino acids are asparagine, aspartic acid and alanine. The physiologically acceptable amino acid may more preferably be alanine. It is understood throughout the present invention that the physiologically acceptable amino acid is present as a physiologically active optic isomer, such as L-alanine. Alanine has been used as an example in the present invention. WO 96/05867 shows a general effect of other amino acids, such as glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine. The contrast agent may comprise morethan one physiologically acceptable amino acid. Decisive for the choice of amino acid or amino acids are the price and the stability as well as the taste, appearance and odour of the amino acid to have a product acceptable to the patients. As regards the other uptake promoter, vitamin D, successful MRI has been performed when the vitamin D is vitamin D₃.

The contrast agent used in the invention is particularly suited for use as a dispersion in an aqueous medium. Thus, in the method of the first aspect, in step a the contrast agent may be provided by dispensing the manganese (II) compound, the amino acid and the vitamin D in water. In the second and third aspects, the manganese (II) compound, the amino acid and the vitamin D may be dispensed in water.

In order to improve shelf-life of the contrast agent, it is desirable to keep some of its ingredients separate during storage. Thus, in the method of the first aspect, prior to dispensing the manganese (II) compound, the amino acid and the vitamin D in water, the manganese (II) compound may be present in a first container, and the amino acid and the vitamin D may be present in a second container. In the second and third aspects, the manganese (II) compound may be present in a first container, and the amino acid and the vitamin D may be present in a second container. It is possible to formulate the contrast agent immediately or shortly prior to administration by combining the uptake promoters, amino acid and vitamin D, with the manganese (II) compound. For the case that the manganese (II) compound is MnCI₂, it is suitable to store it as its tetrahydrate form.

The contrast agent used in the invention may comprise further uptake promoters. The contrast agent used in the invention may include components other than uptake promoters, such as an amino acid and a vitamin D, and the manganese (II) compound, for example conventional pharmaceutical formulation aids, such as wetting agents, buffers, disintegrants, binders, fillers, flavouring agents and liquid carrier media, such as sterile water, water/ethanol etc.

The pH of the contrast agent when dispersed in an aqueous medium is preferably in the acidic range, e.g. about 2 to 7, and while the amino acid may itself serve to yield a composition with this pH, buffers or pH adjusting agents may be used.

The contrast media may be formulated in any edible/drinkable medium and in conventional pharmaceutically administrable forms, such as tablets, capsules, powders, solutions, dispersions, syrups, etc.

Brief description of the drawings

Fig. 1 is an illustration of the results of the Example below and shows relative signal intensity (%) of liver parenchyma (Sl Liver / SI Fat) over time (hours) for a lower dose (dashed line, thick error bars) and a higher dose

(continuous line, thin error bars) of a manganese (II) based contrast agent.

Fig. 1 by courtesy of Dr. med. Matthias Rief, lnstitut fϋr Radiologie, Charite-

Universitatsmedicin Berlin, 10117 Berlin, Germany.

Fig. 2 shows sample magnetic resonance images obtained 0 hours (a), 1 hour (b), 2 hours (c), 3 hours (d), and 6 hours (e) after administration of a manganese (II) based contrast agent in the Example below. Example

Purpose

The aim of this study was the investigation of magnetic resonance imaging of the liver and the characterization of the signal changing effects after oral application of two different dosages of a manganese (II) based contrast agent.

Materials and methods A study population of ten patients received MRI (magnetic resonance imaging) of the upper abdomen at 1.5 tesla (Magnetom Avanto, Siemens Medical Solutions, Erlangen, Germany) using a 6-channel phased array surface coil and the spine-array coils. Time points for the MR examinations were chosen at 0 hours (before administration of contrast agent), at 1 hour, at 2 hours, at 3 hours and at 6 hours after oral application of a manganese (II) based liver-specific contrast agent. Either a lower dose (n=5) or a higher dose (n=5) was applied (lower dose corresponds to 0.8 g manganese chloride tetrahydrate, 0.5 g alanine and 800 IU vitamin D₃; higher dose corresponds to 1.6 g manganese chloride tetrahydrate, 1 g alanine and 1600 IU vitamin D₃). Hepatic metastases were confirmed by a biphasic CT (computed tomography) scan between 14 and two days in advance. The study was approved by the local ethical review board.

A breath hold T1 -weighted fast low-angle shot (FLASH) sequence (TR: 218 ms; TE: 4.72 ms; flip angle 90°; field of view 350 x 420 mm; slice thickness 7 mm; 6/8 partial fourier) was performed at each time point. Signal intensities (Sl) of liver and metastases were determined in regions of interest. The relative signal-to-tissue ratio (liver relative to fat) was calculated for the quantitative evaluation in the left hepatic lobe. Further the contrast between liver and lesion was calculated using the equation: contrast = [SI_P - SI_L] / [SI_P + SIL] with P representing the SI of the liver parenchyma and L representing the SI of the focal hepatic lesion. The non-parametric Wilcoxon signed rank test and Mann-Whitney-U test were used for the statistical analysis. Results

Signal intensities (Sl) of the liver parenchyma relative to SI of fat over time are illustrated as percentage-values in Figure 1. Sample images are given in Figure 2. First, already one hour after administration of the contrast agent a significant increase of the signal intensity (Sl) of the liver parenchyma relative to SI of fat was detectable compared to unenhanced (0 hours, i.e. before administration of contrast agent) images. A maximum was reached after three hours in both groups (3 hours: 85.5% ± 8.7% in the lower dose group and 88.7% ± 9.8% in the higher dose group).

Second, there was no significant difference between both groups at each time point (p>0.15).

Third, a significant change and increase in the contrast between liver and lesion could be detected starting after two hours in both groups (p<0.05; lower dose 0.29 ± 0.10 and higher dose 0.33 ± 0.11) and remaining stable up to six hours (p<0.05; lower dose 0.33 ± 0.11 and higher dose 0.32 ± 0.14).

Conclusions

Application of both the lower and the higher dose of the oral manganese (II) based liver-specific contrast medium showed a significant enhancement of liver SI in T1w abdominal imaging. Combining high relative signal intensity of liver parenchyma relative to fat in the according sequence with significant increase of liver-lesion contrast for diagnostic accuracy, we unexpectedly found the time period between two and six hours after oral application of the contrast agent to be best, suggesting a well suited time window for magnetic resonance imaging of the liver in this time period.

It is to be understood that the invention is not to be limited to the exemplified embodiments but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

Claims

1. Method for examination of the liver of a human patient, comprising the following sequential steps: a) providing a contrast agent comprising a physiologically acceptable non- chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D; b) administering the contrast agent orally or gastrically to the patient; and c) subjecting the patient to magnetic resonance imaging of the liver about 1-6 hours after administration of the contrast agent.

2. Method according to claim 1 , wherein the patient is subjected to magnetic resonance imaging of the liver about 2-6 hours, preferably about 3-6 hours or about 3.5-6 hours, and more preferably about 4-6 hours or about 4.5-6 hours, after administration of the contrast agent.

3. Method according to claim 1 or 2, wherein the contrast agent is administered orally.

4. Method according to any one of the preceding claims, wherein the contrast agent is administered in a dose providing about 1-10 mmol manganese (II), preferably about 2-5 mmol manganese (II), and more preferably about 2-4 mmol manganese (II), to the patient.

5. Method according to any one of the preceding claims wherein the contrast agent is administered in a dose providing about 25-150 μmol manganese (ll)/kg body weight, preferably about 50-125 μmol manganese (ll)/kg body weight, and more preferably about 50-100 μmol manganese (ll)/kg body weight, to the patient.

6. Method according to any one of the preceding claims, wherein in the contrast agent the molar ratio of manganese (II) to amino acid is about 1 :1 to 1 :3, preferably about 1 :1 to 1 :2, and more preferably about 1 :1.2 to 1 :1.6.

7. Method according to any one of the preceding claims, wherein in the contrast agent the ratio of vitamin D to manganese (M) is about 50-1000 IU vitamin D/mmol manganese (II), preferably about 100-500 IU vitamin D/mmol manganese (II), and more preferably about 150-250 IU vitamin D/mmol manganese (II).

8. Method according to any one of the preceding claims, wherein the manganese (II) compound is a water soluble manganese (II) salt.

9. Method according to claim 8, wherein the physiologically acceptable non-chelate water soluble manganese (II) salt is MnCI₂.

10. Method according to any one of the preceding claims, wherein the physiologically acceptable amino acid is selected from the group consisting of alanine, valine, leucine, tryptophan, methionine, isoleucine, proline, phenylalanine, serine, glycine, threonine, cysteine, asparagine, glutamine, tyrosine, aspartic acid, glutamic acid, arginine, lycine and histidine; preferably is selected from neutral amino acids including asparagines and aspartic acid; and more preferably is alanine.

11. Method according to any one of the preceding claims, wherein the vitamin D is vitamin D₃.

12. Method according to anyone of the preceding claims, wherein in step a the contrast agent is provided by dispensing the manganese (II) compound, the amino acid and the vitamin D in water.

13. Method according to claim 12, wherein prior to dispensing the manganese (II) compound, the amino acid and the vitamin D in water, the manganese (II) compound is present in a first container, and the amino acid and the vitamin D is present in a second container.

14. Method according to claim 9 and claim 12 or 13, wherein prior to dispensing the manganese (II) compound in water, the manganese (II) compound is present as its tetrahydrate form.

15. Contrast agent comprising a physiologically acceptable non-chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D for use, in examination of the liver of a human patient, by oral or gastrical administration to the patient about 1-6 hours before subjecting the patient to magnetic resonance imaging of the liver.

16. Contrast agent according to claim 15, wherein administration occurs about 2-6 hours, preferably about 3-6 hours or about 3.5-6 hours, and more preferably about 4-6 hours or about 4.5-6 hours, before subjecting the patient to magnetic resonance imaging of the liver.

17. Contrast agent according to claim 15 or 16, further defined as in any one of claims 3 to 11.

18. Contrast agent according to any one of claims 15 to 17, wherein the manganese (II) compound, the amino acid and the vitamin D are dispensed in water.

19. Contrast agent according to any one of claims 15 to 17, wherein the manganese (II) compound is present in a first container, and the amino acid and the vitamin D is present in a second container.

20. Contrast agent according to claim 17 or 19 and defined as in claim 9, wherein the manganese (II) compound is present as its tetrahydrate form.

21. Use of a physiologically acceptable non-chelate manganese (II) compound, a physiologically acceptable amino acid and a vitamin D for the manufacture of a contrast agent for examination of the liver of a human patient by oral or gastrical administration to the patient about 1-6 hours before subjecting the patient to magnetic resonance imaging of the liver.

22. Use according to claim 21 , wherein administration occurs about 2-6 hours, preferably about 3-6 hours or about 3.5-6 hours, and more preferably about 4-6 hours or about 4.5-6 hours, before subjecting the patient to magnetic resonance imaging of the liver.

23. Use according to claim 21 or 22, further defined as in any one of claims 3 to 11.

24. Use according to any one of claims 21 to 23 wherein the manganese (II) compound, the amino acid and the vitamin D are dispensed in water.

25. Use according to any one of claims 21 to 23, wherein the manganese (II) compound is present in a first container, and the amino acid and the vitamin D is present in a second container.

26. Use according to claim 23 or 25 and defined as in claim 9, wherein the manganese (II) compound is present as its tetrahydrate form.