DIORADIN REFUSED RECOGNITION
Report of the Council on Pharmacy and Chemistry
A preparation called Dioradin was placed on the market as a cure for consumption three years ago in Europe and somewhat later in this country. It was first submitted to the Council in July, 1911. Because of the manifestly unwarranted claims made for its use in the treatment of tuberculosis, the Council voted that the product be refused recognition for conflict with Rule 8, without at that time taking under consideration the question whether or not it was in conflict with other rules of the Council.
In June, 1912, further consideration of Dioradin was requested. The American agent having promised a reform in the methods of advertising, the Council considered the available evidence regarding the identity and value of the preparation. Examination of evidence regarding the composition of Dioradin—claimed to consist of radium chlorid, iodoform and menthol in an ether-oil solution—showed serious discrepancies as to the amount of radium as well as to the identity and amounts of other constituents. It was further found that the experimental evidence was insufficient and biased. Then, too, in view of the difficulty of judging the effects of medicines in tuberculosis, the clinical data were unconvincing. There was nothing to prove that the reported improvements, even if they actually occurred, were to be ascribed to the mixture as a whole rather than to any one of its constituents.
As a result of these findings, the Council voted that Dioradin be refused recognition and that the publication of these facts be authorized. In accordance with its regular procedure, it also submitted the report to the agent. In reply the agent submitted evidence which showed that he was not responsible for the misstatements about Dioradin but offered no facts that affected the Council’s findings.
The entire matter having been referred to a second referee, minor modifications of the first draft of the report were authorized. Since then the Dioradin Company has submitted two reports of examinations of Dioradin made for the company in Germany showing a higher radium content than that previously found. These reports do not alter the facts brought out in the report of the Council that the composition of Dioradin has been variable, which past variability arouses a feeling of uncertainty or lack of confidence. In view of this the amended report was ordered published and appears below.
W. A. Puckner, Secretary.
FIRST SUBMISSION OF DIORADIN
Dioradin, a preparation for the treatment of consumption originated by Dr. R. de Szendeffy, Budapest, Hungary, was submitted to the Council by Louis Gero, Ltd., New York, with the following statement of composition:
“A radio-active preparation of Menthol, Iodin and Radium Barium Chlorid 1⁄10 of a drop; in ether solution.”
A circular which accompanied the submission stated:
“Preparation No. 3 of Dioradin contains not only terpins but also iodin salts.... In view of the fact that emanations of the radium as well as the combinations of the evasive iodin terpins enter into the organism through the lung....”
Later these indefinite statements of composition were supplemented by the following:
| “In 100 c.c. there are: | |
| 1 | gr. Iodoform. |
| 5 | " Menthol. |
| 10 | drops Radium chlorid solution (1 milligr. in 100 c.c. of water). |
| 5 | gr. ether. |
| 90 | " Oil (ol. amygd. frig. press).” |
In a circular contained in the package these claims were made:
“The preparations of the Dioradin are based on the miraculous effects which scientific researches have shown in regard to the different sicknesses treated with radium.
“It is generally known that radium, even if externally employed, has proved itself to be a bactericidal remedy. Its effect is multiplied if one employs it internally even in infinitesimal doses, in consequence of its permanent action of emanation on the organism.
“The preparations of the Dioradin contain the radium itself. For this reason their antiseptic and bactericidal effect is much more intensive than with medicaments which contain only its emanation, which disappears in a short time.”
In view of the general extravagance of the claims made for its therapeutic action the preparation was rejected without considering other possible conflicts with the rules of the Council.
SECOND SUBMISSION OF DIORADIN
Having been advised of the rejection by the Council of Dioradin the American agency, which in the meantime had become the Dioradin Co., requested further consideration. The Council therefore took up the subject again. After certain typographical errors had been corrected the following was now given as the composition:
| “1 | gram Iodoform. |
| 5 | grams Menthol. |
| 10 | drops Radium Chlorid Solution (containing 1 milligram of radium chlorid in 100 cubic centimeters of water). |
| 5 | grams Ether. |
| 89 | grams expressed oil of almond. |
| This liquid is put up in ampules containing one cubic centimeter of liquid.” | |
In support of the therapeutic claims for Dioradin the American agent submitted literature consisting chiefly of articles by Dr. Bernheim of Paris. Before reporting on the requested reconsideration of Dioradin the referee directed the secretary of the Council to point out to the American agent that in the formula given, the amount of non-volatile matter should be about 90 per cent., whereas the report of the Lederle Laboratories which accompanied the request for reconsideration states that but 72.08 per cent. was found in the analysis. In reply the agent stated that he had called the attention of Dr. Szendeffy (the originator of Dioradin) to the discrepancies concerning non-volatile matter and that he felt sure the discrepancy was wholly accidental (sic). In a later communication the agent submitted a statement of analysis from the Lederle Laboratories of a new specimen of Dioradin according to which the amount of non-volatile matter agreed essentially with the amount claimed by the agent.
The referee, having examined the evidence, is of the opinion that the statement of composition is misleading and that the therapeutic claims are unwarranted, thus:
DISCREPANCIES IN RADIUM CONTENT
The chief claims for its therapeutic value are based on the radium content, yet the discrepancies and contradictions, regarding this are serious.
In connection with the reconsideration of this product the agent presented a certificate of chemical examination by the Lederle Laboratories in which the following statement was made as to the radio-activity:
“Examination shows the preparation to possess slight radioactivity, corresponding in activity to less than 1-10,000 of 1 milligram of radium bromid per ampule. According to the sworn statement of Dr. A. de Szendeffy, the originator of Dioradin, the preparation contains 10 drops of radium chlorid solution (1 milligram in 100 cubic centimeters of water) in 100 cubic centimeters of the preparation. This would correspond to 5-1,000 milligram of radium chlorid in 100 cubic centimeters, or about 1-20,000 of 1 milligram per ampule.”
A cursory reading of this paragraph gives the impression that Dioradin possesses fully the amount of radio-activity claimed by its originator, Dr. A. de Szendeffy. This impression is greatly strengthened by the concluding paragraph of the Lederle report, which says:
“In conclusion, our examination shows that the preparation submitted to us as Dioradin possesses radio-activity, and contains a fixed oil (apparently expressed oil of almond), iodoform, menthol and ether, thus confirming the sworn statement of Dr. A. de Szendeffy in regard to the composition of this product.”
On inquiry as to the method used by the Lederle Laboratories, in determining radio-activity the agent submitted a further statement of the Lederle Laboratories which describes the gamma ray test by which the determination was made and a radium value equivalent to 0.000041 mg. of radium bromid per capsule was obtained. The report then says:
“The variations of the single measurements from the mean in the case of the natural leak and the leak with the Dioradin near were so large that we did not feel justified in assigning much accuracy to the figure, 0.000041, but stated that the amount of radium per capsule could not be greater than 0.0001 mg., with the possibility of there being a much smaller amount present.”
It is evident that the wording of the reports of the Lederle Laboratories is liable to give the impression that their examination confirms the claims made for Dioradin.
It is further evident from these reports that the amount of radio-active matter has not been definitely ascertained but that it is at the best very small. The unreliability of the claims for radium content of Dioradin was recently shown by Buechner,[43] who found a specimen obtained from an apothecary to contain but 1-1,000 of the amount claimed.
VOLATILE AND NON-VOLATILE MATTER
The varying claims regarding the content of volatile and non-volatile matter throw doubt on the entire composition of Dioradin, for if the statement as to these is wrong the rest of the statement regarding composition cannot be given credence.
In the first submission of Dioradin about 89 per cent. of non-volatile matter was claimed but in the report of the analysis by the Lederle Laboratories, which accompanied the resubmission, only about 72 per cent. was found. Later the Lederle Laboratories reported that an examination of a new specimen of Dioradin had shown about 90 per cent. of non-volatile matter. The discrepancies between the composition claimed for Dioradin and that found for the product in the first Lederle report has shown that the agent was quite ignorant of the composition of the product which he was selling.
INDEFINITENESS OF THE IODIN CONTENT
The label on the trade package of Dioradin first submitted to the Council stated that the product contained iodoform; a similar statement was made in the submission of the product; the circular accompanying the first submission stated that “iodin salts” were contained in the product while the iodin content was referred to further on in this circular as “combinations of evasive iodin terpins.” In Bernheim’s papers, which have been used to advertise Dioradin, and which are referred to in the same circular, the iodin compound is called “iode peptonisé,” which, according to information stated by the American agent to have come from Budapest, is to be translated “iodized peptone.” What is the meaning of this confusion? One would naturally suppose that the preparation to be sold in this country contains iodoform in an ether-oil solution while the one used by Bernheim and Dieupart[44] was stated to contain an ethereal solution of “iodized peptone.” This is another mystification, for an ethereal solution of any kind of peptone would be a novelty. The matter is of some importance, for Bernheim and Dieupart lay great stress on the difference between “peptonized iodin” and other iodin (loc. cit., p. 333) and of the superiority of ethereal over oily solutions (loc. cit., p. 334). The American agents, however, in the second submission, state that this is all a mistake; that the Dioradin used by Bernheim is the same Dioradin which was submitted to the Council; and that this does not contain, and never did contain, the ethereal solution of “iode peptonisé” to which Bernheim attached so great importance. Bernheim (report to Medical Congress of Lyons) himself has come to the same conclusion; for five months after his first paper he believes that the “special salt of radium” (sic) is the principal agent; so that the “peptonized iodin” must be unimportant, and in a cablegram of July 4, 1912, he now informs the Dioradin Company that the formula was incorrectly given in his first papers “owing to my ignorance of actual composition,” and that all the Dioradin used by him was of the composition stated in the submission to the Council.
While this vindicates the good faith of the American Dioradin Company, it does not clear up the mystery. The question occurs at once: What led Dr. Bernheim to make such positive statements? Was he drawing purely on his imagination? If so, why did his imagination take this peculiar special direction? Or if he did have some reason to imagine the “iode peptonisé,” who supplied this reason? And if, at that time, he was given to understand by Szendeffy, who must have supplied him with the material, that it contained the iodized peptone, how can he be positive at this time, that it did not contain it? Has he actually analyzed the old material?
There is also a further question which needs to be answered. Why has Dr. Szendeffy waited until Dioradin was rejected by the Council before correcting Bernheim’s serious misapprehension, in the meantime permitting the circulation of Bernheim’s paper?
Until these questions have been satisfactorily answered, the element of mystery about the composition of Dioradin cannot be cleared away.
EXPERIMENTAL EVIDENCE
The available experimental evidence regarding “Dioradin” is restricted to some quotations from its inventor Szendeffy, in the paper of Bernheim and Dieupart (p. 334). These, if confirmed, would show that radium alone has practically no effect on cultures of tubercle or colon bacilli; that 0.1 gm. of “iode-menthol” (concentration not stated) checks the growth of the acid-fast organisms; and that this antiseptic efficiency can be nearly doubled by the addition of a little radium. No quantitative data are given, so that it is difficult to judge the accuracy of the observation. Granting that it is correct, it would have little bearing on the therapeutic actions of Dioradin, for there is nothing to show that the effective test-tube concentration is reached in the pulmonary tissues.
It is also claimed that the injection of Dioradin prevents tubercle infection. The referee believes that the Council and the medical profession should hesitate to accept this conclusion without further details; and these would require confirmation by unprejudiced observers.
CLINICAL EVIDENCE
The Dioradin Company submits considerable clinical data in favor of Dioradin. It must be remembered that most favorable opinions have been published, from time to time, about scores of “consumption cures,” which have mysteriously lost their efficiency when their novelty wore away. There is no more reason to doubt the good faith of those who are enthusiastic about Dioradin than of those who have been enthusiastic about other “cures.” There appear to be features in the course of tuberculosis which make the judgment of therapeutic measures peculiarly difficult. It is possible that impartial clinical trials of Dioradin by tuberculosis experts appointed by the Council might facilitate judgment as to the actual efficiency of Dioradin. The referee doubts, however, whether this would advance the Council very much toward the acceptance of the substance. Such an investigation would be so lengthy that it should not be undertaken until the Dioradin Company itself has offered at least presumptive evidence in this direction, especially in view of the adverse report recently made by Cecil Wall.[45] Ten tuberculous patients were treated by Wall in strict accordance with the method outlined to him by Bernheim, yet Wall concludes that none of the cases, though treated accurately in accordance with the instructions, can be quoted to justify any of the claims for the therapeutic efficiency of Dioradin. The Council cannot undertake lengthy investigations of this character until it is put in possession of data which would show to its satisfaction that such investigations would probably be fruitful.
CONCLUSIONS
From investigations made, it appears that the claims in regard to the composition of Dioradin have contained vague statements and contradictions which arouse a feeling of uncertainty and lack of confidence. Until this uncertainty is cleared away, Dioradin cannot be considered as complying with Rule 1. The experimental data are insufficient and unconvincing. Some favorable clinical reports have been submitted, but the accuracy of the observations is to be questioned and they are more than offset by the negative results observed by Cecil Wall. As might be expected, other negative results, if observed, have not been submitted and there is nothing in the manufacturer’s claim to show whether the improvement reported is really due to the peculiar mixture called Dioradin or to any one of its ingredients.
It is therefore recommended that Dioradin be not accepted for New and Nonofficial Remedies. In view of the extensive advertising of this preparation and because of the admittedly incorrect statements in the earlier papers it is recommended that publication of this report be authorized.—(From The Journal A. M. A., Oct. 26, 1912.)