US2704270A - Antihistaminic injectable X-ray contrast media - Google Patents

Description

United States Patent ANTlI -IISTAMDIIC INJECTABLE X-RAY CONTRAST MEDIA' Olle Gunnar Anton Olsson, Lazarettet, Lund, Sweden, gssignor to Aktiebolaget Leo, Halsingborg, Sweden, a

No Drawing. Application April 16, 1951,

er a No- .21.3

4 Claims. or. 167-95 This invention relates to new compositions of matter suitable for use for X-ray contrast purposes and more particularly it relates to such compositions of matter in the form of an aqueous solution.

Intravenous injections of water soluble X-ray contrast media containing 3.5-diiodo-4 pyridon-N-acetic acid or salts of the same are occasionally followed by undesired secondary effects such as bouts of coughing or sneezing, flashing of the face and neck, decrease'i'n blood pressure, vomiting, lacrymatio'n, salivation, urticaria, shock effects and cyanosis and even in severe cases death.

Anattempt to exclude patients where undesired secondary effects might be expected on the base of anamnesis of allergy'and on the 'base of previous tests carried out in a similar manner as the tests for identifying allergic diseases are of little value, as these precautions provide no guarantee that the undesired secondary effects will not really occur. Furthermore, the exclusion of patients on the base of anarnnesis of allergy or previous tests may result in' the exclusion of patients who might tolerate the injection. According to an article by Crepea, Allanson and de Lambre, New York State Journal of Medicine, 1949, vol. 49, part 2, pages 2556-2558, attempts have been made 'to avoidthe undesired secondary effects caused by intravenous injection of 3.5-diiodo-4-pyridon-N-acetic acid diethanolamine by previous oral administration of N.N-dimethyl-N-benzyl-N-(apyridyl)-ethylenediamine hydrochloride or l-phenyl-l- (2-pyridyl)-3-dimethylaminopropan without any success. The authors conclude: Premedication with pyribenzamine or trimeton did not seem to influence the incidence, severity or type of the reactions to 3.5-diiodo-4- pyridon-N-acetic acid.

One object of the present invention is to enable 3.5-diiodo-4-pyridon-N-acetic acid or its water soluble salts to be used for X-ray contrast purposes in such a manner that the above named undesired secondary effects are avoided or greatly reduced. A further object of the invention is to procure aqueous solutions containing 3.5-diiodo-4-pyridon-N-acetic acid or a water soluble salt thereof, which solutions are suitable for use for X-ray contrast purposes by intravenous injection and which are of such a character that the number of cases in which undesired secondary effects follow the injection is greatly reduced and the severity of the secondary effects if any is clearly less than in the case when solutions of said contrast medium of the kind hitherto known have been administered.

With these objects in view and with further objects in view which will appear from the following I shall now proceed to describe the preferred embodiments of my invention.

The invention consists generally in procuring an aqueous solution containing 3.5-diiodo-4-pyridon-N- acetic acid or salts thereof in a concentration suitable for use for X-ray contrast purposes together with a clinically applicable antihistaminic substance. It has been found that the power of reducing the undesired secondary effects following intravenous injections of X-ray contrast media of the said type is not limited to any special chemical configuration, but is a general property, although to a varying degree, of a class of chemically quite different substances having in common their power of producing antihistaminic effects. Excellent results have been obtained with an aqueous solution of 3.5-diiodo-4-pyridon- N-acetic acid diethanolamine and fl-dimethylamino ethyl acetic acid diethanolamine may be substituted wholly or in part by 3.S-diiodo-4-pyridon-N-acetic acid diethylamme.

Most advantageously the antihistaminic substance is introduced into the solution in such a proportion which s just sufficient to secure the desired effect, viz. eliminatmg or reducing the undesired secondary effects followm'g intravenous injection of X-ray contrast media of the above named type. Excellent results are obtained in case the proportion of a salt of 3.S-diiodo-4-pyridon-N-acetic acid and the antihistaminic substance is such that a quantity of the solution containing the quantity of the X-ray contrast medium usually or maximally used for one in jection contains at the same time a quantity of the antihistaminic substance sufficient to secure an effect if used intravenously in the combatting of allergic diseases such as urticaria. This means that in this embodiment of the invention ,d-dimethylamino ethyl benzhydryl other hydro.- chloride is used in amounts from 20-200 mgs per dosis of the X-ray contrast medium whereas the other antihistaminic substances mentioned above, i. e., 2-phenylbenzylamino-rnethylimidazoline hydrochloride, N'-pmethoXy-benzyl -N pyridyl-N dimethyl ethylenediamine hydrochloride and N dimethylarnino isopropylthiodiphenylamine hydrochloride are used in amounts from about -400 milligrams per dosis of the X-ray contrast medium. The antihistaminic substance may also be used in smaller amounts in which case, however, the undesired secondary effects may not be avoided to the same extent. On the other hand I have not found it necessary to use the'antihistaminic substances in greater proportions than those stated above since I have found no surplus advantage being obtained in the way of eliminating or reducing the secondary effects of the X-ray contrast medium and the undesired secondary eifects of the antihistaminic substances such as dizziness etc. may then occur.

Instead of hydrochlorides of the antihistaminic substances mentioned above the free bases themselves may be used with excellent results or addition salts of the said bases with other suitable organic or inorganic acids than hydrochloric acid. Suitable acids are those which are innocuous and therapeutically acceptable to the organism, for instance sulphuric acid and ascorbic acid. Whether used as the free bases or as salts with acids other than hydrochloric acid, the antihistaminic substance is to be used in amounts equivalent to those stated for the hydrochlorides.

The X-ray contrast medium consisting in salts of 3.5- diiodo-4-pyridon-N-acetic acid is used in the concentration and the quantity normally employed intravenously for diagnostic purposes, i. e. a concentration of 35-70 per cent. In the solution containing the antihistaminic substance the following salts of the X-ray contrast me dium may be introduced by Way of example in the proportions mentioned in the following: diethanolamine salt of 3.5-diiodo-4-pyridon-N-acetic acid: 40.5 per cent and diethylamine salt of 3.S-diiodo-4-pyridon-N-acetic acid: 9.5 per cent; or diethanolamine salt of 3.5-diiodo-4-pyridon-N-acetic acid: 70 per cent; or diethanolamine salt of 3.5-diiodo-4-pyiidon-N-acetic acid: 34-36 per cent.

I have found that the amount of antihistaminic substance necessary to secure the desired effect is independent of the concentration of the specific salt of the 3.5- diiodo-4-pyridon-N-acetic acid as well as of the total concentration of salts in the solution and furthermore that it is unnecessary to increase the amount of antihistaminic substance beyond those stated above even in the cases where extraordinary great intravenous injections of the X-ray contrast medium are given.

Very satisfactory results have been obtained by the injection of an aqueous solution containing 3.5-diiodo- 4-pyridon-N-acetic acid diethanolamine and fl-dirnethyl- Cases with- Cases with percent Group 25325: out secondsecondary secondary p ary efiects effects cfiects The patients in groups A and B received an intravenous injection of 20 milliliters of an aqueous solution containing 35 per cent W/V of 3.5-diiodo-4-pyridon acetic acid diethanolamine, the preparations being from two diiferent manufacturers. The patients in group C received an intravenous injection of 20 milliliters of an aqueous solution containing 35 per cent W/V of 3.5-diiodo-4-pyridon acetic acid diethanolamine+20 milligrams of B-dimethylaminoethyl benzhydryl ether hydrochloride.

Among the patients in groups A and B were none with auarnnesis of allergy. in group C patients with anamnesis of allergy were not excluded. The secondary effects observed in group C were less severe than those observed in groups A and B.

The compositions of matter according to the invention may be prepared in the following way: An aqueous solution of the contrast medium is prepared in a concentration greater than that desired for the final composition. This solution is thereupon mixed with an aqueous solution of an antihistaminic substance in such an amount as to secure the desired concentration of the contrast medium in the resulting mixture. It is very satisfactory to use the antihistaminic substance in such an amount that each intravenous dose of the resulting mixture will contain a quantity corresponding to that used intravenously for the combatting of allergic diseases.

No changes in the pharmacologic properties of the compositions of matter according to the invention have been observed even if the compositions have been kept for more than one year.

I claim:

1. As a new pharmaceutical composition for intravenous injection an aqueous solution containing e-dialkylaminoethylbenzhydryl ether and at least one salt of 3,5-diiodo-4-pyridon-N-acetic acid as an intravenously injectable X-ray contrast medium.

2. A new pharmaceutical composition for intravenous injection as set forth in claim 1, the X-ray contrast medium being at least one amino salt of 3,5-diiodo-4-pyridon-N-acetic acid.

3. A new pharmaceutical composition for intravenous injection as set forth in claim 1 containing the fl-dialkylaminoethyl-benzhydryl ether in an amount of about 20 to 200 milligrams per dose of the X-ray contrast medium.

4. As a new pharmaceutical composition for intravenous injection an aqueous solution containing 35% W/V 3,5-diiodo-4-pyridon-N-acetic acid diethanolamiue and fi-dimethylaminoethyl-benzhydryl ether hydrochloride in such an amount that each intravenous dose of the solution contains 20 milligrams of the latter.

References Cited in the file of this patent UNITED STATES PATENTS Reitmann Mar. 5, 1935 Taplin Dec. 5, 1950 OTHER REFERENCES

Claims (1)

1. AS A NEW PHARMACAUTICAL COMPOSITION FOR INTRAVENOUS INJECTION AN AQUEOUS SOLUTION CONTAINING B-DIALKYLAMINOETHYLBENXHYDRYL ETHER AND AT LEAST ON SALT OF 3,5-DIODO4-4PYRIDON-N-ACETIC ACID AS AN INTRAVENOUSLY INJECTABLE X-RAY CONTRAST MEDIUM.