SELS D'ACIDE ISEFAMIQUE POUR TOMOGRAPHIE HEPATIQUE PAR ORDINATEUR

SALTS OF ISEFAMIC ACID FOR COMPUTER TOMOGRAPHY OF THE LIVER

Abrégé anglais

PROCESS FOR ENHANCED COMPUTED
TOMOGRAPHY OF THE LIVER
Abstract of the Disclosure
A method for computed tomography of the liver
utilizing a water soluble salt of 5,5'-(sebacoyldiimino)-
bis-(2,4,6-triiodo-N-methyl)-isophthalamic acid as the
contrast agent to improve the detection of abnormal tissue.

Revendications

WHAT IS CLAIMED:
1. A method for CT scanning of the liver to
detect abnormal liver tissue from normal liver tissue comprising
intraveneously introducing into a living animal body in a
sufficient amount to provide enhancement of the density of
normal liver tissue a radiological composition containing as
the contrast agent to enhance the density of said tissue the
sodium or meglumine salt of a compound represented by the
following formula:
<IMG>
in a pharmaceutically acceptable intraveneous vehicle and
thereafter performing a CT scan of the liver.
2. A method according to Claim 1 wherein the
contrast agent is the dimeglumine salt,
3. A method according to Claim 1 wherein the
contrast agent is the disodium salt.
4. A method according to Claim 1 wherein the
contrast agent is a mixture of the sodium and meglumine
salt.

Description

;5;~
SALTS OF ISEFAMIC ACID FOR COMPUTER
TOMOGRAPHY OF THE LIVER
Background of the Invention
The present invention relates to a process for
computed tomography of the liver.
The recent advent of computed tomography (CT)
equipment for whole body diagnostic examinations including
the liver provides greater anatomic detail and requires
less x-ray contrast agent than with conventional x-ray
equipment. Attempts have been made to use known x-ray
contrast agents to improve CT examinations of the liver,
for example, water soluble urographic x-ray contrast
agents, e.g., diatrizoate or iothalamate, but their use
has not been totally satisfactory. These agents remain
intravascular until extracted by the kidneys and are not
specifically distributed to the liver. They will enhance
liver vasculature but they are not extracted by the hepato-
cytes. Therefore, as urinary excretion progresses these -
agents rapidly clear the liver within five to fifteen
minutes without having achieved the selective tissue con-
centrations required to demonstrate small hepatic tissue
abnormalities. An iodinated oil emulsion has demonstrated
effective uptake into the liver in animal and human studies,
however, its toxicity and side effects have precluded its
use in routine clinical practice. Although it might be
expected that intravenous cholangiographic agents typified
by iodipamide would demonstrate utility for this purpose
since they must be transported through liver tissue to be

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excreted into the bile where they find their current
clinical utility as cholangiographic agents, they have
been unsatisfactory~ Effective intravenous cholangio-
graphic agents all possess significant choleretic activity
permitting their rapid excretion into the bile and hence
their utility. This same choleretic activity precludes
the accumulation of these contrast agents in functional
liver tissue to an extent which would make them useful
in CT studies of the liver.
An object of the present invention is to provide
a process for computed tomography of the liver utilizing
a contrast agent to enhance the detection of abnormal
tissue.
In accordance with this invention there is pro-
vided a process for enhanced CT scanning of the liver to
detect abnormal liver tissue from normal liver tissue com-
prising intravenously introducing into a living animal
body in a sufficient amount to enhance the density of
normal liver tissue, an intravenous radiological composi-
tion containing as the contrast agent a physiologically
acceptable water soluble salt, e.g., sodium or meglumine,
of the compound represented by the following structure:
ÇOOH COOH
CH3-NH-C ~ -NH-C-(CH2)8-C-NH- ~ -C-NH-CH3
O I O O
5,5'-(sebacoyldiimino)-bis-(2,4,6-triiodo-N-
methyl)-isophthalamic acid also known as
iosefamic acid
or mixtures of such salts in a pharmaceutically accept-
able vehicle and thereafter performing a CT scan of the

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liver. After administration, the contrast agent becomes
concentrated in normal liver tissue but to a much lesser
degree in abnormal liver tissue. Additionally, the con-
trast agent remains in normal liver tissue for extended
periods of time. Consequently, abnormal liver tissue
can be differentiated from normal liver tissue by CT
scanning. The density of the normal liver tissue is
enhanced to a much greater degree than the density of
abnormal liver tissue. Thus, the attenuation value of
normal liver tissue is higher than that of abnormal liver
tissue and abnormal liver -tissue can be detected with a
high degree of certainty.
The water soluble salts useful in the process
of this invention are described in U.S. Patent 3,290,366.
Example ~ describes the preparation of the acid and the
salts may be prepared in the usual way, e.g., by
neutralization.
The radiological compositions used in the present
invention contain at least one of the above-mentioned salts
as the contrast agent together with a pharmaceutically
acceptable intravenous vehicle.
Suitable intravenous vehicles include aqueous
buffer solutions, sterile water for injection, physiological
saline, and balanced ionic solutions containing chloride
and/or bicarbonate salts of normal blood plasma cations
such as calcium, sodium, potassium or magnesium. Concen-
tration of these salts in the pharmaceutically acceptable
vehicle may vary.

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In accordance with this invention, the radio-
logical composition is intravenously introduced into a
living animal body in a sufficient amount to enhance
the density of normal liver tissue so that this tissue
can be differentiated from abnormal liver tissue during
CT scanning. Generally, these compositions are admini-
stered to provide a dose of iodine of about 100 mg to
about 400 mg of iodine per kg of living animal body weight.
The radiological composition is administered so
that the contrast agent remains diagnostic in the living
animal body for about 0.5 to about 5.0 hours although both
shorter and longer resident periods are normally accept-
able. Thus, the compounds may be formulated in vials or
ampules containing 10 to 100 ml of an aqueous solution.
The radiological compositions may be used in
the usual way for CT scanning procedures, for example,
a sufficient amount of the composition to provide enhance-
ment of the density of normal liver tissue is injected
into a living animal body and then the liver is scanned
with a suitable whole body scanner. Such scanners are
commercially available from various manufacturers such as
General Electric, Pfizer, EMI, etc.
CT scanning of the liver of dogs was carried
out utilizing the dimeglumine salt of iosefamic acid.
The acid was prepared generally in accordance with the
directions set forth in U.S. Patent 3,290,366. The
dimeglumine salt was prepared by neutralization of the
acid and then formulated into a solution having a concen-
tration of 75% w/v. The procedures for these scans and

the results are described in the paper entitled "Iosefamate
Meglumine: An Iodinated Contrast Agent For Hepatic Cornputed
Tomography Scanning", Radiology, 132:115/118, July 1979.
As can be seen, the contrast agent was selectively concen-
trated and retained by functional hepatocytes during a
period when the concentration in the blood and other body
tissues fell back to normal.