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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to magnetic resonance imaging (MRI) of the human
body and to the use of paramagnetic contrast agents to improve the
diagnostic usefulness of the MR images. More particularly, this invention
is concerned with paramagnetic oil emulsions as MRI contrast agents and
their use in MRI evaluation of the abdomen and pelvis. One important
aspect of this invention is provision of a palatable oral MRI contrast
agent which distributes evenly to provide effective MRI of the distal
bowel to afford good diagnosis of soft tissue abnormalties.
2. Description of the Prior Art
Magnetic resonance imaging is a useful diagnostic tool due to its good
tissue differentiation. The imaging is enhanced by use of paramagnetic
contrast agents which affect the relaxation times T1 (spin-lattice) and T2
(spin-spin) of hydrogen atoms present in the body materials. In abdominal
MRI, bowel loops and intraluminal contents can mimic pathology such as
adenopathy, pancreatic or other retroperitoneal lesions. Therefore, the
development of a reliable MRI contrast agent, preferably a palatable oral
agent, is required before gastrointestinal MRI can assume a major role
clinically.
Current review articles indicate that a problem in gastrointestinal tract
MRI examinations has been stimulation of peristalsis, lack of contrast,
and the lack of acceptable oral contrast agents. Particularly, magnetic
contrast agents have not been developed for small bowel lumen. Clanton,
Jeffrey A., "Oral Contrast Agents,"0 Magnetic Resonance Imaging, Vol. I,
Chap. 48, pp. 830-837, W. B. Saunders Company (1988). Stark, David D. and
Bradley, William G., Jr., "Gastrointestinal Contrast Agents," Magnetic
Resonance Imaging, pp. 1134-1139, The C. V. Mosby Company, St. Louis, Mo.
(1988).
In the past few years, a variety of agents have been advocated as potential
oral MRI contrast agents. However, none of them satisfies all the criteria
of a satisfactory agent including: uniform effect throughout the
gastrointestinal tract; good patient acceptance; no side effects; and
ability to mix freely with intestinal contents. The potential oral MRI
contrast agents that have been proposed can be divided into four different
categories.
The first group includes miscible positive agents, such as MnCl.sub.2,
Burnett, K. R., Goldstein, E. J., Wolf, G. L., Sen, S., and Mamourian, A.
C., "The Oral Administration of MnCl.sub.2 : A Potential Alternative to IV
Injection for Tissue Contrast Enhancement in Magnetic Resonance Imaging,"
Magnetic Resonance Imaging, Vol. 2, pp. 307-314, Pergamon Press, Ltd.
(1984); Mamourian, A. C., Burnett, K. R., Goldstein, E. J., Wolf, G. L.,
Kressel, H. Y. and Baum, S., "Proton Relaxation Enhancement in Tissue Due
to Ingested Manganese Chloride: Time Course and Dose Response in the Rat,"
Physiological Chemistry and Physics and Medical NMR, 16, pp. 123-128
(1984); dilute iron aqueous solutions such as Geritol.RTM., ferric
ammonium citrate, Wesbey, G. E., Brasch, R. C., Goldberg, H. I., and
Engelstad, B. L., "Dilute Oral Iron Solutions as Gastrointestinal Contrast
Agents for Magnetic Resonance Imaging; Initial Clinical Experience,"
Magnetic Resonance Imaging, Vol. 3, pp. 57-64 (1985); metal chelates,
Runge, V. M., Stewart, R. G., Clanton, J. A., Jones, M. M., Lukehart, C.
M., Partain, C. L., and James, A. E., Jr., "Work in Progress: Potential
Oral and Intravenous Paramagnetic NMR Contrast Agents," Radiology, Vol.
147, No. 3, pp. 789-791 (Jun., 1983): 0.06% solution of ferric chloride,
Young, I. R., Clarke, G. J., Bailes, D. R., Pennock, J. M., Doyle, F. H.,
and Bydder, G. M., "Enhancement of Relaxation Rate with Paramagnetic
Contrast Agents in NMR Imaging", Computed Tomography, 5, pp. 543-546
(1981); protein and very low iron concentration to delineate soft tissue
of the stomach, duodenum and jejunum, Chen, B., Gore, J. C., Zhong, J. H.,
McCarthy, S., Lange, R. C., Helzberg, J., Young, R. S. K., and Wong, M.,
"Gastrointestinal MRI Contrast Enhancement by Liquid Food", Proc. of the
7th Annual Meeting of the Society of Magnetic Resonance in Medicine, San
Francisco, Calif., Aug. 20-26, pp. 733 (1988): low amounts of iron in
infant formula drinks, Bisset III, G. S., "Evaluation of Potential
Practical Oral Contrast Agents for Pediatric Magnetic Resonance Imaging",
Pediatric Radiology, 20, pp. 61-66 (1989); and Gd-DTPA with mannitol,
Laniado, M., Kornmesser, W., Hamm, B., Clauss, W., Weinmann, H-J., and
Felix, R., "MR Imaging of the Gastrointestinal Tract: Value of Gd-DTPA,"
Amer. Jour. of Roentgenology, 150:817-821 (Apr., 1988). Oral contrast
agents in aqueous solutions including osmotically active material, such as
mannitol, are taught by U.S. Pat. No. 4,719,098. The disadvantages of
these agents include significant dilutional effect from gastric, biliary
and pancreatic secretions in the proximal small bowel resulting in failure
to show effects distal to the ligament of Treitz, patient non-acceptance
of metallic taste, complex absorptive process in the distal small bowel
resulting in unpredictable and varying concentrations in the GI tract, and
in the case of Gd-DTPA with mannitol some patients experienced diarrhea,
probably due to the osmotic effect of mannitol.
The second group includes immiscible negative agents such as ferrite
particles, Widder, D. J., Edelman, R. R., Grief, W. L. and Monda, L.,
"Magnetite Albumin Suspension: A Superparamagnetic Oral MR Contrast
Agent," Amer. Jour. of Roentgenology, 149:839-843 (Oct., 1987); Hahn, P.
F., Stark, D. D., Saini, S., Lewis, J. M., Wittenberg, J., and Ferrucci,
J. T., "Ferrite Particles for Bowel Contrast in MR Imaging: Design Issues
and Feasibility Studies," Radiology, 164, pp. 37-41 (Jul., 1987); and U.S.
Pat. No. 4,731,239 which depends upon cellular metabollic processes for
MRI signal enhancement. Micellular particles such as phospholipid vesicles
enclosing a paramagnetic material as contract agents for NMR imaging is
taught by U.S. Pat. No. 4,728,575. These vesicles are targeted to
accumulate in tumor tissue after intravenous injection. Aqueous
suspensions of particles of water insoluble paramagnetic compounds
suitable for oral or rectal administration for gastrointestinal NMR
imaging are taught by U.S. Pat. No. 4,615,879. U.S. Pat. No. 4,675,173
teaches use of encapsulated ferromagnetic contrast agents in critically
sized microspheres of protein, carbohydrate or lipid biodegradable matrix
for intravenous administration and segregation in the liver and spleen for
magnetic resonance imaging. Superparamagnetic metal oxides coated with
polysaccharides are taught to be biologically degradable and a contrast
agent for MRI by U.S. Pat. No. 4,827,945. The disadvantages of this group
include the fact that with high concentrations, the homogeneity of the
magnetic field may be distorted and produce image artifacts. This is
especially detrimental in gradient echo imaging.
The third group includes immiscible positive agents such as aqueous oil
emulsions: Li, K. C. P., Tart, R. P., Storm, B., Rolfes, R., Ang, P., and
Ros, P. R., "MRI Oral Contrast Agents: Comparative Study of Five Potential
Agents in Humans," Proceedings of the Eighth Annual Meeting of the Society
of Magnetic Resonance in Medicine, Amsterdam, Aug. 18, 1989, p. 791;
European Patent Publication 0,245,019 teaches low density contrast medium
of oil in water emulsion which may contain soluble salts (sodium chloride)
or sugars (dextrose) to maintain homeostasis in the intestine and points
out problems of unopacified bowel loops. The major disadvantage of this
group is that even with very concentrated oil emulsions, the enhancement
effect is not adequate when T1 weighted pulse sequences are used.
The use of oils and high lipid liquid to increase NMR contrast is known:
Newhouse, J. H., Brady, T. J., Gebhardt, M., Burt, C. T., Pykett, I. L.,
Goldman, M. R., Buonanno, F. S., Kistler, J. P., Hinshaw, W. S. and
Pohost, G. M., "NMR Imaging: Preliminary Results in the Upper Extremities
of Man and the Abdomen of Small Animals", Radiology, Vol. 142, No. 1, pp.
246 (Jan. 1982) teaching use of mineral oil; Paula T. Beall, "Safe Common
Agents for Improved NMR Contrast" Physiological Chemistry and Physics and
Medical NMR, No. 16, pp. 129-135 (1984) teaching use of olive oil. Corn
oil emulsions for use as a negative density oral contrast agent for
imaging bowel wall in CAT scan is taught by Raptopoulos, V., Davis, M. A.,
and Smith, E. H., "Imaging of the Bowel Wall: Computed Tomography and Fat
Density Oral-Contrast Agent in Animal Model", Investigational Radiology,
21, pp. 847-850 (1986) and Raptopoulos, V., Davis, M. A., Davidoff, A.,
Karellas, A., Hays, D., D' Orsi, C. J. and Smith, E. H., "Fat Density Oral
Contrast Agent for Abdominal CT", Radiology, 164, pp. 653-656 (1987). Corn
oil is taught to be a useful oral negative contrast agent for pancreas CAT
scans by Baldwin, G. N., "Computed Tomography of the Pancreas: Negative
Contrast Medium", Radiology, 128, pp. 827-828 (1978).
The fourth group includes immiscible negative agents such as CO.sub.2 gas
tablets, Weinreb, J. C., Maravilla, K. R., Redman, H. C., and Nunnally,
R., "Improved MR Imaging of the Upper Abdomen with Glucagon and Gas," J.
Comput. Assist., Tomog. 8, pp. 835-838 (1984), perfluorocarbons, Mattrey,
R. F., Hajek, P. C., Gylys-Morin, V. M., Baker, L. L., Martin, J., Long,
D. C., and Long, D. M., "Perfluorochemicals as Gastrointestinal Contrast
Agents for MR Imaging: Preliminary Studies in Rats and Humans", Amer.
Jour. of Roentgenology, 148, pp. 1259-1263 (Jun., 1987); Mattrey, R. F.,
"Perfluorooctylbromide: A New Contrast Agent for CT, Sonography, and MR
Imaging," Amer. Jour. of Roentgenology, 152:247-252 (Feb., 1989), and
kaolin-pectin, Li, K. C. P., Tart, R. P., Storm, B., Rolfes, R., Ang, P.,
and Ros, P. R., supra. This group has high potentials. However, CO.sub.2
is limited to applications to the proximal GI tract. Perfluorocarbons are
not FDA approved yet for clinical use and kaolin-pectin may cause severe
constipation in the dosages suggested.
Iron as a dietary requirement is known: infant milk formulas containing
very low amounts of iron are known from U.S. Pat. No. 4,216,236; solid fat
encapsulated food particles containing ferric ammonium citrate, vitamins,
minerals or mixtures thereof to provide increased dietary assimilable
iron, vitamins, minerals or mixtures thereof are taught by U.S. Pat. No.
3,992,555.
SUMMARY OF THE INVENTION
This invention relates to a paramagnetic oil emulsion suitable for enteric
administration wherein the emulsion comprises about 5 to about 30 volume
percent oil, preferably about 15 to about 25 volume percent oil, and about
70 to about 95 volume percent, preferably about 75 to about 85 volume
percent, aqueous based paramagnetic agent carrier and having therein a
magnetic resonance contrast effective and less than a toxic amount of at
least one paramagnetic agent. In one preferred embodiment, a water-soluble
paramagnetic agent is dissolved in the aqueous based paramagnetic agent
carrier. By the terminology "aqueous based or aqueous paramagnetic agent
carrier" we mean to include any aqueous media in which the paramagnetic
agent may be dissolved and which forms an emulsion with the oil. The
aqueous based paramagnetic agent carrier is an active carrier in
enhancement of even distribution of paramagnetic agent, particularly in
distal bowel regions, and preferably includes nutritious materials such as
milk and, for oral administration, includes flavor enhancers, such as ice
cream or similar aqueous based materials to render the oil emulsion
acceptable for human oral ingestion. Inclusion of an aqueous based carrier
such as ice cream, in addition to flavor enhancement, provides emulsifiers
for stabilization of the oil emulsion over long periods of time. Milk and
ice cream aid in obtaining desired distribution of the paramagnetic agent,
particularly in lower bowel regions of adults. One skilled in the art can
readily ascertain the "magnetic resonance contrast effective and less than
a toxic amount" of paramagnetic agent suitable for us with the
paramagnetic oil emulsion of this invention, depending upon the specific
paramagnetic agent used. Suitable amounts are those providing desired
magnetic resonance image contrast while not inflicting any toxic or
undesirable effects to the patient. We have found when using ferric
ammonium citrate, a preferred paramagnetic agent, that about 0.75 to about
3 grams total dosage is required for positive enhancement throughout the
small bowel of adults for gradient echo and spin echo magnetic resonance
sequences. For adults, ferric ammonium citrate can be given in doses from
1 to 2 grams three or four times daily (The United States Dispensatory,
25th Edition, J. B. Lippincott Co., 1955) or up to 6 grams daily
(Martindale, The Extra Pharmacopoeia, 28th Edition, The Pharmaceutical
Press, London, 1982).
This invention includes a method of imaging a body cavity, such as abdomen
and pelvis, of a patient by magnetic resonance after administration,
preferably oral, to the patient of a magnetic resonance contrast medium as
described above. Particularly, the invention includes a method for
obtaining an in vivo magnetic resonance image of the abdomen and/or pelvis
of a human subject by administering to the subject an effective amount of
a paramagnetic oil emulsion as described above and obtaining the magnetic
resonance image after a time period sufficient to allow the paramagnetic
oil emulsion to pass to the desired portion of the gastrointestinal tract.
The paramagnetic oil emulsion is preferably administered orally and/or
rectally and effective distribution through the small intestine occurs
within about 30 to about 180 minutes post oral administration, and almost
immediately in the colon post rectal administration. Oral ingestion is
preferably carried out over about 90 minutes prior to scanning for a good
distribution of contrast agent in the small intestine. Glucagon may be
administered in amounts of about 0.2 to 0.6 mg. intramuscularly
immediately prior to scanning to provide good control of motion artifacts.
Even distribution of the paramagnetic oil emulsion occurs through the
gastrointestinal tract increasing the magnetic resonance signal intensity
difference between the gastrointestinal tract and other abdominal organs
or pathologic tissues without loss of anatomical detail.
The combination of oil-in-water emulsion and paramagnetic agent according
to this invention, results in a synergism unobtainable by either alone,
namely, even distribution and good magnetic resonance image
intensification, particularly in distal bowel regions of adults. Preferred
embodiments provide a palatable oral dosage which is high in patient
acceptability and diagnostic reliability.
DESCRIPTION OF PREFERRED EMBODIMENTS
The paramagnetic oil emulsion of this invention may be formulated using
about 5 to about 30, preferably about 15 to about 25, volume percent,
based upon the product paramagnetic oil emulsion, of any physiologically
compatible oil. We have found that emulsions, wherein the oil comprises
predominantly over 50 and up to 100 volume percent vegetable oil, function
satisfactorily. In preferred embodiments, the vegetable oil may be
selected from corn, olive, peanut, soybean, and mixtures of such oils.
Corn oil is a particularly preferred oil. We have found that for most
commonly used magnetic resonance spin echo and gradient echo pulse
sequences the intensity of the corn oil emulsions peaks at about 15 to
about 25 volume percent corn oil. We have found, using corn oil, that
paramagnetic oil emulsions comprising less than about 5 volume percent
oil, based upon the total paramagnetic oil emulsion, result in patchy
distribution in the small bowel, especially in the distal small bowel of
an adult. Using above about 10 volume percent corn oil results in even
distribution in the small bowel and we have found that about 20 volume
percent corn oil is acceptable in taste while providing consistent even
distribution in the small bowel. We have also observed that none of the
unmixed components of the paramagnetic oil emulsions of this invention has
a high signal intensity with all pulse sequences: SPIN ECHO 550/22, SPIN
ECHO 2000/90, FLASH 40/18/10.degree., FLASH 40/18/30.degree., FLASH
40/18/50.degree., FLASH 40/18/70.degree., and FLASH 40/18/90.degree..
The aqueous paramagnetic agent carrier portion of the paramagnetic oil
emulsion of this invention may be formulated using about 70 to about 95,
preferably about 75 to about 85, volume percent, based upon the product
paramagnetic oil emulsion, and may comprise any physiologically compatible
aqueous solution. It is preferred that the aqueous paramagnetic agent
carrier be nutritious and of desirable taste. In preferred embodiments,
the aqueous paramagnetic agent carrier comprises milk and a flavor
enhancer, such as ice cream or like flavoring components. We have found
milk, or chemically similar, aqueous based material to aid in the even
distribution of a water soluble paramagnetic agent, particularly in the
small bowel region. We have found that where the aqueous paramagnetic
carrier comprises about 20 to about 60 volume percent milk and about 20 to
about 40 volume percent ice cream, based upon the total of the oil
emulsion, the taste of the paramagnetic oil emulsion is very acceptable to
human patients. Other similar flavor enhancers may be used. Ice cream is a
particularly preferred flavor enhancer since it also contains emulsifiers
which provide very long-time stability to the paramagnetic oil emulsion
and enhances distribution of the paramagnetic agent, particularly in the
small bowel.
Suitable paramagnetic agents for use in this invention are solubilized in
at least one phase of the oil-in-water emulsion according to this
invention. The paramagnetic agent may be completely solubilized in either
the aqueous or oil phase or may be present in both the aqueous and oil
phases. In one preferred embodiment, water soluble paramagnetic agents are
dissolved in the water phase of the paramagnetic oil emulsion of this
invention. Paramagnetic agents known to the art may be used in a magnetic
resonance image contrast effective and less than a toxic amount. The
magnetic resonance image contrast effective an toxic amount of specific
paramagnetic agents will be known to those skilled in the art, and if not,
can be ascertained by routine experimentation. In preferred embodiments,
the paramagnetic agent comprises an iron-based material. A particularly
preferred water-soluble paramagnetic agent is ferric ammonium citrate.
Many currently used well-known paramagnetic agents are suitable for use in
this invention, such as ferric ammonium citrate, gadolinium-DTPA,
chromium-DTPA, chromium-EDTA, manganese-DTPA, manganese-EDTA, manganese
chloride, iron sulfate and mixtures thereof. We have found, using the
paramagnetic oil emulsion of this invention, that the magnetic resonance
signal intensity peaks with use of ferric ammonium citrate present in the
form of Geritol.RTM. at about 7.5 to about 12.5 volume percent
Geritol.RTM., based upon the total paramagnetic oil emulsion. We have
found for small bowel MRI in adults using the paramagnetic oil emulsions
of this invention that the total dose of 1 gm ferric ammonium citrate (at
2 gms/l) produced good enhancement with gradient echo pulse sequences but
variable enhancement in different subjects with the T1 weighted spin echo
pulse sequences while the total dose of 3 gms ferric ammonium citrate (at
6 gms/l) produced good enhancement with all gradient echo and spin echo
pulse sequences normally used. At a concentration of 6 gms/l, a mild
metallic aftertaste was present which was easily masked by chewing gum or
candy. The preferred dosage for oral administration is about 2 to about 3
gms ferric ammonium citrate at a concentration of about 4 to about 6
gms/l.
Thickening agents may be used to increase the viscosity of the paramagnetic
oil emulsion of this invention to enhance distribution throughout the
small bowel. Suitable thickening agents include those of the fibrous or
film type, such as Metamucil, gelatin, methyl cellulose, agar, pectin and
mixtures thereof. Suitably, about 2 to about 8 percent thickening agent
may be used. We have found about 25 to about 60 gms Metamucil/liter oil
emulsion to be suitable.
The aqueous based paramagnetic agent carrier and/or the paramagnetic agent
may be provided in dehydrated dry powder form and mixed with water for
formulating the paramagnetic oil emulsion. The paramagnetic oil emulsions
of this invention may be formulated by mixing the oil and aqueous based
paramagnetic agent carrier with the paramagnetic agent in a blender, such
as a Waring blender, at high speed for about two to five minutes. The
paramagnetic oil emulsions will be stable for a time period sufficient to
allow administration and imaging of a body cavity of a patient by magnetic
resonance after enteric administration. However, physiologically
compatible emulsifiers, such as are well-known to the art, for example as
included in ice cream, may be added to the mixture which is emulsified to
provide long-term storage stability of the emulsion.
The paramagnetic oil emulsion according to this invention may be used for
imaging a body cavity of a patient by magnetic resonance after
administration to the patient of a magnetic resonance contrast medium of
the above described paramagnetic oil emulsion. In preferred embodiments in
vivo magnetic resonance images of the gastrointestinal tract of a human
subject may be obtained by administering orally to the subject an
effective amount of a paramagnetic oil emulsion, as described above,
followed by obtaining the magnetic resonance image after a time period
sufficient to allow the paramagnetic oil emulsion to pass to the desired
portion of th gastrointestinal tract. Methods of obtaining magnetic
resonance images of gastrointestinal tracts are known to those skilled in
the art and preferred methods are set forth in the following specific
examples.
We have found using a paramagnetic oil emulsion of this invention
comprising 0.9 gm ferric ammonium citrate, 100 cc corn oil, 150 cc ice
cream, and 250 cc homogenized milk that even distribution throughout the
small bowel of an adult is obtained from 1 hour to 2 hours post a single
oral administration to provide excellent gradient echo imaging. However,
when spin echo imaging which requires longer imaging time is used, a
multiple oral administration scheme is preferred, such as splitting the
dosage into four or five oral administrations over a period of about 90
minutes prior to imaging. A preferred oral ingestion scheme is even
proportions of the dose at 90 min., 60 min., 30 min., 15 min., and
immediately prior to scanning.
We have found that motion artifacts may be significantly reduced in MRI
according to this invention when an adult is additionally administered
about 0.2 to about 0.6 mg glucagon prior to MR scanning, preferably about
0.3 to about 0.4 mg glucagon intramuscular immediately prior to scanning.
This administration is effective, free from side effects and easy to
administer.
One preferred paramagnetic oil emulsion according to this invention has the
formulation in volume percent: 38% milk, 30% ice cream, 20% corn oil, 12%
Geritol.RTM.. We have found this formulation provides a safe, effective
MRI contrast agent with high patient acceptance for oral administration.
We have found using this formulation that the entire small bowel becomes
homogeneously brighter than surroundings when imaged with all commonly
utilized magnetic resonance spin echo and gradient echo pulse sequences.
We have found intensity enhancement to be much stronger using Gd-DTPA or
ferric ammonium citrate based paramagnetic agents than when using ferrous
sulfate.
Another preferred paramagnetic oil emulsion according to this invention for
oral administration comprises about 2 to 3 gms/500 ml dosage, preferably
about 3 gms/500 ml, ferric ammonium citrate, about 15 to about 25,
preferably about 20 volume percent corn oil, about 20 to about 40,
preferably about 30 volume percent ice cream, and about 40 to about 60,
preferably about 50 volume percent homogenized milk which results in
excellent MRI enhancement by even distribution throughout the small bowel
of adult humans.
The specific examples set forth embodiments of the invention in detail
which are intended to be illustrative only and are not intended to limit
the invention in any way.
EXAMPLE I
An aqueous/oil emulsion paramagnetic contrast agent according to one
preferred embodiment of this invention was formulated by mixing the
following components for 3 minutes in a blender at high speed to form 500
ml of the paramagnetic oil emulsion:
______________________________________
Component Volume Percent
______________________________________
Homogenized Milk 38
Melted ice cream (Breyer vanilla, 8% fat)
30
Corn oil (Mazola) 20
Geritol .RTM. J.B. Wlliams Co.
12
3.38 mg/ml Fe.sup.+3 (ferric ammonium citrate)
0.16 mg/ml thiamine
0.16 mg/ml riboflavin
3.38 mg/ml niacinamide
0.13 mg/ml panthenol
0.03 mg/ml pyridoxine
1.69 mg/ml methionine
3.38 mg/ml choline bitartrate
Ethanol 12 volume percent
______________________________________
Similar emulsions were formulated varying the amount of Geritol.RTM. from 4
to 20 volume percent, the amounts of corn oil and ice cream being constant
and the balance being milk.
EXAMPLE II
Emulsions prepared as described in Example I with varying Geritol.RTM.
content from 4 to 12 volume percent were taken orally by human volunteers
in the amount of 500 ml uniformly over a two-hour period. The volunteers
abstained food and drink for at least four hours prior to ingestion of the
emulsions. The volunteers were asked to grade on a scale of 1 to 5: the
taste of the emulsion (1 being great and 5 being intolerable), the amount
of nausea experienced (1 being none and 5 being severe vomiting), and the
amount of abdominal cramps (1 being none and 5 being severe). The
volunteers also recorded the duration of discomfort, the timing and
frequency of bowel movements and the overall impression of the emulsion
ingestion. Results are shown in Table 1:
TABLE 1
______________________________________
Geritol .RTM.
(% v/v) Taste Nausea Abd. Cramps
______________________________________
4 1 1 1
6 1 1 1
8 1 1 1
10 2 1 1
12 2 1 1
______________________________________
EXAMPLE III
The volunteers who ingested emulsions referred to in Example II were then
imaged using either a 1.5 T Siemens Magnetom MR imager or a General
Electric Signa MR imager. Spin echo (SE) pulse sequences with repetition
time (TR) of 550 msec and echo time (TE) of 22 msec, and TR of 2000 msec
and TE of 90 msec were used. Images were also obtained using gradient echo
FLASH pulse sequences with TR of 50 msec, TE of 15 msec and flip angle of
40 degree pulse sequences. The images were then reviewed jointly by two
radiologists to evaluate the ability of the contrast agent to opacify the
gastrointestinal tract and to enhance delineation of the different
abdominal organs. The delineation of the bowel organs were scored on a
scale of 1 to 5, 1 being very poor and 5 being excellent, the results
being tabulated in Table 2:
TABLE 2
__________________________________________________________________________
Geritol .RTM.
% Small Bowel
Organ Delineation
Degree of Bowel Enhancement
(% v/v)
Opacified
with Best Sequence
SE 550/22
SE 2000/90
FLASH 50/15/40
__________________________________________________________________________
4 20 2 1 4 3
6 50 3 2 4 3
8 70 4 3 4 4
10 80 4 4 5 5
12 >90 5 5 5 5
__________________________________________________________________________
EXAMPLE IV
The emulsion prepared as in Example I with 12 percent Geritol.RTM. was
taken in 500 ml dosage orally by five human volunteers in the same manner
as described in Example II followed by MR imaging in the same manner as
described in Example III. The results, using the same scoring system as in
Examples II and III is tabulated in Table 3.
TABLE 3
__________________________________________________________________________
Abd. % Small Bowel
Organ Delin. with
Degree of Bowel Enhancement
Volunteer
Taste
Nausea
Cramps
Opacified
Best Sequence
SE 550/22
SE 2000/90
FLASH 50/15/40
__________________________________________________________________________
1 2 1 1 >90 5 5 5 5
2 2 1 1 >90 5 5 5 5
3 1 1 1 >90 5 5 5 5
4 1 1 1 80 4 5 5 5
5 2 1 1 80 4 5 5 5
__________________________________________________________________________
EXAMPLE V
Paramagnetic agents with various water/oil emulsions were formulated
without ice cream and milk for human tests. In each case using Gd-DTPA 1
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