US2366742A - Detoxicant - Google Patents

Description

Patented Jan. 9, 1945 UNITED STATES PATENT OFFICE DETOXICANT Gustav J. Martin, Elmhurst, and Marvin R. Thompson, Great Neck, N. Y., assignors to William R. Warner dz Company, Inc., New York,

N. Y., a corporation of Delaware N Drawing. Application May 3, 1941,

Serial No. 391,722

Claims. (01. 167-65) amount of the drug that may be administered inthe treatment of such a disease or infection, however, is usually less than the amount that would obtain the maximum, or in many cases a suilicient or desirable therapeutic effect, because of the toxic action of the drug on the human being or other animal body to which it is administered.

This is one of the principal difliculties involved in the administration of the sulfa type drugs. many cases where the disease is advanced, the patient cannot tolerate a sufficient amount of the drug to check the action of the micro-organisms because of the toxic action on the patient of such an amount. In other cases the tolerance of the patient is so low as to make it impossible to use an effective amount of the drug, and it therefore cannot be used as a. therapeutic measure.

By sulfa". type compounds werefer to the sulfonamides and sulfones. A very large number of such compounds have been investigated and have been recognized as a class and shown to have a similar therapeutic value, although some are more significant in this respect than others. The more important of the sulfonamide Promin, are the most important.

It is an object of our invention to provide a The substituents (2-sulfanilamidotherapeutic agent comprising a sulfa compound which is non-toxic or of reduced toxicity and which can be administered in greater amounts in most cases, or at least in the usual amounts, without an objectionable toxic effect on the human being or other animal being treated.

, As is apparent from the above description, the sulfa compounds havetwo characteristics; one

is its therapeutic efiect achieved through its action on the micro-organisms and the other is its toxic effect resulting from the poisoning action of the compound on the animal body. It would be relatively simple to modify the sulfacompound or its action so as to alter its toxicity as well as its therapeutic effect. However, it is not a simple matter to alter one of these characteristics without altering the other, i. e., to alter the toxicity without destroying the therapeutic effect.

The action and theory of detoxication has in generalbeen appreciated heretofore, and a detoxifying material is'usually thought to combine or coact with a drug in such a manner as to mask the toxic characteristic. But this is desirable only when the characteristics of the compound that are responsible for the therapeutic effect are left unaltered. The exact action of various materials is little known, and the nature of detoxicants, ortheir action with a particular drug so as to affect its therapeutic action, cannot be predicted from any available knowledge.

We have discovered that if a hexuronic acid or a salt thereof is administered at the same time as any of the sulfa compounds, the toxic properties of the compound on the animal system are eliminated or greatly reduced and minimized, but at the same time the therapeutic effect of the compound is not appreciably interfered with, It is possible therefore to give a dosage of the sulfa compound which is effective in its action against the micro-organisms without adversely affecting the patient. While no attempt will be made to describe all of the improved results obtained in accordance with the invention, one important action of the hexuronic acid in the de toxication which may be mentioned is the prevention of acetylation of the sulfa type compound and the accompanying urolithiasis.

It is a further object of our invention,-therefore, to provide a therapeutic agentcomprising a sulfa compound in combination with a hexuronic acid or a salt thereof.

We have previously discovered, as described in co-pending applications, that certain of the sulfa compounds can be detoxified with certain other compounds which achieve an optimum eflect, but

2 this optimum effect in many instances requires a different detoxicant for the different sulfa compounds. In the case of sulfanilamide, however,

the optimum detoxifying action is obtained with group of compounds is readily apparent.

In accordance with our invention, the sulfa compound may be admixed in the desired proportions with the hexuronic acid or salt thereof, in either a dry mixture or in solution. This mixture or solution may then be administered in the same way that sulfa compounds are normally administered, namely, orally, parenterally, rectally, etc. While the hexuronic acid or salt thereof may be administered to the human body separately. from the sulfa compound, we find it more convenient to administer them as a mixture since thisassures that the proper amount of both ingredients will be administered at the same time, and also eliminates the necessity for administering two drugs which would be less convenient and might give rise to misunderstanding as to the amount and nature of the administration.

Upon being taken into the body, the sulfa compound and the hexuronic acid or its salt coact or react to produce the non-toxic, therapeutic effect. If desired, the sulfa compound and the hexuronic acid may be reacted in the laboratory in order to provide a single new compound which may be administered to produce the non-toxic therapeutic effect. Such compounds are hitherto unknown.

Hexuronic acids all have the formula CHO(CHOH)4COOH, the different acids being stereoisomers. The most important are glucuronic and galacturonic acids. The more important salts are the alkali metal and alkaline earth metal We claim:

1. A therapeutic agent for use in connection with the treatment of diseases caused by microorganisms, comprising a sulfa type compound effective in combating said micro-organisms and disease, in admixture with a. material to lower the toxicity of said sulfa type compound without materially impairing the therapeutic effect thereof selected from the group consisting of hexuronic acids having the general formula CHO (CHOH) 4COOH and their salts.

2. A therapeutic agent for use in connection with the treatment of diseases caused 'by microorganisms, comprising a p-amino benzene sulfonamide effective in combating said micro-or- Ca(OOC(CI-IOH) 4CHO) 2 to lower the toxicity of said sulfonamide without materially impairing the therapeutic effect thereof.

salts, for example, sodium, potassium and calcium glucuronate, particularly the latter.

The proportions of the materials are not critical, since hexuronic acids may be taken into the body in relatively large amounts without any harmful action. The upper limit of the proportion of the hexuronic acid in our composition is therefore very high, although as a practical matter, in most instances, there is a maximum amount beyond which enhanced results are not obtained. Very small amounts of hexuronic acids or salts thereof obtain improved results, and there is no minimum below which some improvement is not achieved. The proportions may also vary somewhat depending upon the tolerances and peculiarities of the patient with respect to the particular sulfa compound. In general, however, we find a mixture comprising 1 to parts of a hexuronic acid or its salt in admixture with 5 parts of a sulfa compound to be'suitable in most instances. Satisfactory results are usually obtained when the mixture comprises equal parts. It will be apparent that we have provided therapeutic material having superior and advantageous non-toxic properties, as described in the specification and following claims forming a part thereof.

This application is -a continuation-in-part of application Serial No. 334,654, filed May 11, 1940.

4. A therapeutic agent for use in connection with the treatment of; diseases caused by microorganisms, comprising sulfathiazole effective in combating said micro-organisms and disease, in admixture with a material to lower the toxicity of said sulfathiazole without materially impairing the therapeutic effect thereof, selected from the group consisting of glucuronic acid having the general formula CHO(CHOH)4COOH and its salts.

5. A therapeutic agent for use in connection with the treatment of diseases caused by microorganisms, comprising sulfapyridine effective in combating said micro-organisms and disease, in admixture with a material to lower the toxicity of said sulfapyridine without materially impairing the therapeutic effect thereof, selected from the group consisting of glucuronic acid having the gerleral formula CHO(CHOH) iCOOH and its sal s.

6. A therapeutic agent for use in connection with the treatment of diseases caused by microorganisms, comprising sulfanilamide effective in combating said micro-organisms and disease, in admixture with a material to lower the toxicity of said sulfanilamide without materially impairing the therapeutic effect thereof selected from the group consisting of hexuronic acids having the general formula CHO(CHOH) 4COOH. and their salts.

7. A therapeutic agent for use in connection with the treatment of diseases caused by microorganisms, comprising sulfanilamide effective in combating said micro-organisms and disease, in admixture with a material to lower the toxicity of said sulfanilamide without materially impairing the therapeutic effect thereof selected'from the group. consisting of glucuronic acid having thet general formula CHO(CHOH) 4COOH and its sa s.

8. A therapeutic agent for use in connection 2,868,742 with the treatment of diseases caused by microorganisms, comprising sulfanilamide effective in combating said micro-organisms and disease, in

the group consisting of hexuronic acids having their salts.

the general formula cnownomicoon and their salts.

10. A therapeutic agent for use in connection with the treatment of diseases caused by microorganisms, comprising suliapyridine effective in combating said micro-organisms and disease, in admixture with a material to lower the toxicity of said sulfapyridine without materially impairing the therapeutic effect thereof, selected from the group consisting of hexuronic acids having the general formula. CHO(CHOH)4COOH and GUSTAV J. MARTIN.

R. THOMPSON.