CA1143652A - Salts of isefamic acid for computer tomography of the liver - Google Patents

Abstract

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.

Description

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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 ~ ~3~

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 s~

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.

Claims (4)

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:

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.