The present application is directed to the use of X-ray contrast media that act as universal antigens that are labeled herein as "pseudoantigens." X-ray contrast media have the potential to exist in an aggregated state that is greater in increased concentrations. In this aggregated state, contrast media assume the role of multivalent antigens and can successfully compete with any other antigens involved in antibody-antigen reactions that lead to anaphylaxis. In this competition, the large quantity of contrast media serves to inhibit the adverse effects of antibody-antigen reactions without the contrast media itself creating antibodies or creating toxicity problems.

SUMMARY OF THE INVENTION

The present invention is directed to the use of contrast media or modified contrast media molecules (for example contrast molecules with the iodine removed--see FIG. 7B) as drugs that can be utilized to inhibit allergic reactions. The toxicity of the contrast media that is proposed is very low in comparison to almost all drugs on the market and the details of the toxicity of these substances are well known through extensive utilization and research. The contrast media that are proposed are in the dimer and nonionic form and thus are known to be the least toxic of contrast media.

Some possible applications of these "rescue" molecules have been suggested in the body of this application. They will include exploration of their application in human allergic conjunctivitis and in allergic rhinitis. They will also include exploration of their use in status asthmaticus, in "rush" immunotherapy and in routine immunotherapy. A possible use in non-responding cases of anaphylaxis will also be considered. In all of these applications the ability of the contrast molecules to constructively compete with known antigens for their respective antibodies should reduce the number of times when allergic events result in serious consequences. All of this can be accomplished without fear that the contrast molecules will themselves result in the production of antibodies.

Aspects of the present invention are described in the paragraphs below:

1. The use of X-ray contrast media to inhibit, treat or prevent an allergic reaction in a mammal suffering from an allergic reaction by administering X-ray contrast media to such mammal.

2. The use of paragraph 1 wherein the X-ray contrast media inhibits, treats or prevents an allergic reaction by blocking adverse antigen-antibody complex formation.

3. The use of paragraph 1 wherein the X-ray contrast media is selected from the group consisting of dimeric nonionic contrast media or deiodinated nonionic contrast media derivatives.

4. The use of paragraph 1 wherein the X-ray contrast media are in a dimer form.

5. The use of paragraph 1 wherein the X-ray contrast media is non-ionic.

6. The use of paragraph 1 wherein the X-ray contrast media are in an aggregated form.

7. The use of paragraph 1 wherein the X-ray contrast media are administered in a manner selected from the group consisting of subcutaneously, intramuscularly, intravenously or topically.

8. The use of paragraph 1 wherein the X-ray contrast media are triiodinated, completely or partially substituted, benzene moieties existing in the form of a monomer or a dimer.

9. The use of paragraph 1 wherein the antibody is selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4 and IgM.

10. The use of X-ray contrast media for treating anaphylaxis comprised of the step administering from 0.1 grams to 40 grams of X-ray contrast media to a person suffering from any form or degree of anaphylaxis.

11. The use of paragraph 10 wherein the contrast media is any dimeric nonionic contrast media.

12. The use of paragraph 10 wherein the X-ray contrast media is administered subcutaneously in antigen desensitizing therapy to inhibit local or systemic anaphylaxis resulting from the desensitizing antigen.

13. A method of preventing adverse in vivo antigen-antibody complex formation by administering from 0.1 40 grams of X-ray contrast media to a person.

14. The method of paragraph 13 wherein the X-ray contrast media is selected from the group consisting of dimeric nonionic contrast media.

15. A method of treating or preventing allergic conjunctivitis comprised of the steps of administering from 0.1 to 3 ml of dimeric nonionic X-ray contrast media to an eye suffering from allergic conjunctivitis.

16. The method of paragraph 15 wherein the X-ray contrast media is selected from the group consisting of any dimeric nonionic contrast media.

17. The method of paragraph 16 wherein the X-ray contrast media is selected from the group consisting of IOTROLAN and IODIXANOL.

18. The method of treating allergic rhinitis by administering from 0.1 to 3 ml of a dimeric nonionic contrast media by drop installation into the nose in a mammal suffering from allergic rhinitis or exposed to a known potential nasal allergen.

19. The method of paragraph 18 wherein the X-ray contrast media is a dimeric nonionic CM.

20. The method of paragraph 19 wherein the X-ray contrast media is selected from the group consisting of IOTROLAN and IODIXANOL.

DETAILED DESCRIPTION OF THE INVENTION

The phenomenon of antigen-excess has never before been considered in vivo. However, no other intravascular drug is administered at one time in the amount that the contrast media are administered (up to as much as 45 grams in a single injection, etc.). It is believed that the presence of antigens in excess inhibits the likelihood of a single antigen to find empty binding sites on adjacent IgE antibody molecules and thus to produce the release of histamine. An alternative possibility is that the aggregated CM fill the space between adjacent immunoglobulins and prevent the approximation of these molecules and/or their receptors by virtue of steric hindrance. Therefore, the more rapid injection of the contrast media in the dogs is believed to have produced an antigen excess situation relative to the existing IgE antibody on the cells of the dogs from previous sensitization episodes and thus produced less, rather than more, histamine release. Correspondingly, it would no longer appear paradoxical that the contrast media exhibiting the best potential to compete with specific antigens for antibody binding sites in our study of passive hemagglutination inhibition would in fact be the media less likely to produce adverse reactions, rather than the opposite.

Given the above considerations, the question was asked whether contrast media with less potential to compete with antigens in our passive hemagglutination inhibition studies would be more likely to attain antibody-antigen (pseudoantigen) equivalence rather than antigen excess in vivo, and thus be associated with a higher incidence of adverse reactions. This is the case in clinical studies since the ionic monomers, the nonionic monomers, and the nonionic dimers, in that order, needed higher concentrations of concentration-equivalent contrast media to inhibit hemagglutination and range from most toxic to least toxic in the same order. It is thus necessary to consider that the media that are more commonly associated with reactions will be those that are less likely to inhibit hemagglutination in our test and/or are injected in a fashion to produce more dilute contrast solutions.

The significant adverse reactions occurring with contrast media are usually associated with histamine release and a drop in blood pressure. To test the effect on blood pressure in a series of rats, the arterial pressure was monitored following the injection of various contrast media at different concentrations (Lasser, E. C. and Lamkin, G. E. Academic Radiol, 2002, 9 [suppl. 1], S72 S75). These studies were done since it is accepted that the release of histamine from mast cells and/or basophils results in a blood pressure lowering effect. Basal endogenous ongoing histamine release thus effects the prevailing blood pressure and events that increase or decrease histamine release will be associated with a decreased or increased blood pressure.
 

Claim 1 of 8 Claims

1. A method of treating allergic conjunctivitis comprising the step of administering an amount of an X-ray contrast media effective to produce a decrease in histamine release to an eye of a mammal suffering from allergic conjunctivitis, wherein said X-ray contrast media comprises a triiodinated, benzene moiety, wherein said benzene moiety is completely or partially substituted, and wherein said contrast agent is a non-ionic monomer, an ionic monomer, a non-ionic dimer, or an ionic dimer.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.