The Propaganda for Reform in Proprietary Medicines, Vol. 1 of 2

by Council on Pharmacy and Chemistry

DIGALEN OMITTED FROM N. N. R.

Report of the Council on Pharmacy and Chemistry

Digalen is a proprietary said to contain a soluble form (digitoxinum solubile Cloetta) of digitoxin, the chief active principle of digitalis. This preparation was accepted[25] by the Council in 1909 for inclusion in New and Nonofficial Remedies. The Council had not at that time determined whether Digalen contained “soluble amorphous digitoxin,” as claimed, or not. The product was accepted merely as a standardized soluble and fairly stable digitalis preparation.

After the acceptance of Digalen, the therapeutic claims made for it by the manufacturers increased in extravagance. Meanwhile, evidence was brought forward by various independent investigators which tended not only to show that these therapeutic claims were unfounded, but also to discredit the claim that Digalen contained a principle chemically identical with digitoxin. In view of the obscurity of the whole subject of the chemistry of the digitalis principles, the latter claim (that Digalen was a solution of “amorphous digitoxin”) had been an academic issue at the time of the acceptance of the product. When, however, the manufacturers of Digalen sought to mislead physicians by increased and unwarranted therapeutic claims, the Council felt that investigation of the whole matter was imperatively demanded to decide whether or not Digalen should be retained in N. N. R.

The questions at issue were: (1) the presence in Digalen of “amorphous digitoxin”; (2) the constancy of composition and reliability of action of Digalen, and (3) the claim that it causes less gastric disturbance than digitoxin. No satisfactory proof has yet been offered that Digalen contains “amorphous digitoxin.” The mass of evidence tends to show that Digalen is not constant in composition or reliable in action, and that, when given in doses corresponding in therapeutic activity, Digalen causes quite as much gastric disturbance as the official galenical preparations of digitalis.

The outcome of protracted negotiations between the Council and the Hoffmann-La Roche Chemical Works may be summed up as follows: 1. The manufacturers promise to hold in abeyance the claim regarding the presence of “amorphous digitoxin.” 2. They refuse to concede the variable composition of Digalen. 3. They reassert the claim that Digalen is superior to other digitalis products with respect to liability to cause gastric irritation and consequent vomiting.

In view of the unsatisfactory character of the reply on the second and third points, the Council voted that Digalen be omitted from N. N. R. and that publication of the report on Digalen which appears below be authorized, as well as of the two reports[26] (A and B) referred to therein.

W. A. Puckner, Secretary.

Referee’s Report on Digalen

Because of persistent conflict with Rule 6 (unwarranted therapeutic claims) and Rule 1 (composition) it is recommended that Digalen be omitted from New and Nonofficial Remedies; also that a copy of the report be sent to the manufacturers, and that publication of this report and the two previous reports submitted to the Council be authorized.

The nature of the problems involved necessitates a somewhat extended discussion of the subject.

Digalein (liquid) is said to contain 1 part of soluble amorphous digitoxin Cloetta in 1,000 parts of glycerin and 1,600 parts of water with 7.5 per cent. of alcohol. One c.c. is said to contain 0.0003 gm. of the amorphous digitoxin.

Digalen was accepted by the Council[27] and the following footnote was appended to the description in New and Nonofficial Remedies:

“The Council has not determined whether digalen contains ‘soluble amorphous digitoxin’ or not, but accepts it simply as a soluble digitalis preparation.”

Tablets of Digalen were accepted by the Council as a dosage form of Digalen. Each tablet is said to represent 0.5 c.c. (eight minims) of Digalen (liquid).

One of the principal considerations which led the Council to accept Digalen was that it was regarded as affording a fairly constant and stable preparation of digitalis suitable for intravenous administration. If Digalen is not fairly stable and of fairly constant composition it has no obvious advantage over an active soluble digitalis preparation, such as digitalein.

The evidence now at hand seems to show: 1. Digalen is not of constant composition or activity. 2. The manufacturers, or their agents, continue to make misleading statements. 3. It is merely a solution of certain digitalis principles, probably of digitalen mainly, in impure form.

COMPOSITION

Cloetta[28] prepared a soluble amorphous substance which he called “Digitoxinum solubile Cloetta,” but no information concerning the method of preparation has been published.

Cloetta reported the result of an elementary analysis of his product which he compared to the analyses of digitoxin (crystalline) made by Schmiedeberg and by Kiliani, and stated that there could be no doubt concerning the chemical identity of the two substances.

Kiliani[29] characterized as preposterous Cloetta’s claim that the active constituent of Digalen is chemically identical with digitoxin and stated that Digalen was merely an impure digitalein. Kiliani has recently reiterated the statement that the so-called “amorphous digitoxin” is not identical with digitoxin.[30]

Cloetta’s failure to publish his method of preparing Digalen places an additional burden of proof on him (or the manufacturers of Digalen), concerning the identity of the product, and in the face of Kiliani’s denial of the correctness of Cloetta’s contention we must have strong corroborative evidence of Cloetta’s claim before we can accept it as being established.

The difficulties of dealing with the chemistry of digitalis are so well known that they hardly require further mention here, but under the circumstances Cloetta cannot be considered as being wholly unprejudiced, and, while the same might perhaps be said of Kiliani, such evidence as can be deduced tends strongly to support Kiliani’s view, and to disprove the contention of Cloetta.

There is much confusion regarding the names which have been applied to the various principles obtained from digitalis, and while it is undesirable that an established name should be given to a newly discovered principle, one might overlook this if no effort were made to associate the therapeutic actions of the two substances to an extent which the truth did not justify.

While the Council at that time did not challenge the existence of “amorphous digitoxin” and made no attempt to determine the identity with digitoxin of the substance forming the basis of Digalen, the manufacturers of Digalen have sought to show that Digalen and digitoxin were identical so far as their therapeutic actions were concerned, but that Digalen lacked the disadvantages of digitoxin. What was a purely academic question when the acceptance of Digalen was under discussion by the Council becomes a matter of very great practical importance when the manufacturers of Digalen seek to mislead the physician by these claims.

The evidence which lends support to the view that Digalen and digitoxin are wholly dissimilar may be summarized as follows: Digalen differs greatly in its physical properties from digitoxin and in certain of its physiologic actions, as the manufacturers themselves state, Digalen being amorphous, and soluble in water, while digitoxin is crystalline and insoluble in water. The manufacturers state that Digalen differs from digitoxin in certain of its physiologic actions, but the two substances do indeed differ far more than they admit.

Cloetta and the manufacturers of Digalen lay especial stress on the claim that Digalen is cumulative to a far less extent than digitoxin, and that it has far less tendency to cause gastric disturbance than the latter. The first of these claims is true; the second is the very opposite of the truth, as we shall show.

We know nothing of the structure of any of the digitalis principles, and even though one were to admit (purely for the sake of argument) that Digalen and digitoxin were chemical isomers, that fact could not be taken to lend any support to the contention that the two substances were identical, in the face of the established fact that they differ physically and physiologically in nearly every particular, and agree only in that they both cause standstill of the heart in the same way—​an action possessed also by so dissimilar a substance as barium.

The manufacturers of Digalen support the claim of the identity of their product with digitoxin by stating that “Digalen is a solution of the most active glucoside of digitalis.”[31] Of course, it is very generally admitted that digitoxin is the most active principle of digitalis, though there is some question concerning its glucosidal nature.

Digalen is in fact far less active than digitoxin, as has been shown by a number of independent observers[M] (Worth Hale, 1910; Hatcher and Brody, 1910; Neave, 1907; Miller, 1908; the referee; Weis, 1912).

The essential fact which appears from the investigation of Weis is that Digalen did not behave like digitoxin in any case.

Hale also found that Digalen gave atypical actions in which the effects on the central nervous system became prominent. The referee can corroborate these observations of Hale’s on frogs, but the convulsive symptoms were prominent with some specimens of Digalen on mammals, though not with others, the more recent specimens of the preparation showing the action prominently.

The results of all these biologic tests, as well as of the physical tests made by Weis, certainly lend no support to the contention of Cloetta that the potent constituent of Digalen is identical with digitoxin, but, on the contrary, they show conclusively that the two substances differ widely in many essentials, and the continued claim of the manufacturers that the “amorphous digitoxin” said to be contained in Digalen is the same as digitoxin, or that it is the most active glucosid of digitalis, can be considered only as misleading, and therefore in conflict with the rules of the Council.

CONSTANCY OF COMPOSITION AND ACIDITY

The manufacturers of Digalen continue to claim that it is of constant and uniform activity,[32] and they imply this even when they do not state it in those words; for example, a substance cannot be considered reliable if it is variable in activity. “Digalen is Absolutely Reliable. It is Standardized and consequently always uniform. It does not produce gastric disturbances.”

That the foregoing is absolutely untrue can be shown abundantly. Hale[33] found digalen not to be uniformly stable; Weis found very different degrees of activity for Digalen in the liquid and tablet forms, the tablets being but one-third as active as the liquid, and the referee found very great variations in the activity of different specimens of Digalen, one specimen being almost inert. The results obtained by Miller show that Digalen is sometimes very slightly active, or not at all so.

The foregoing citations show conclusively that Digalen is not of uniform activity. When reliability is claimed for Digalen in contrast to the known variability of digitalis, it must be considered as tantamount to the claim that Digalen is not subject to such variability and it must be held that the manufacturers make misleading statements when they assert that Digalen is absolutely reliable.

The manufacturers claim that Digalen does not produce gastric disturbances (see advertisement cited).

It is quite true that when small doses of Digalen are used therapeutically it fails to produce gastric disturbances because it is of such slight activity, as previously stated, but when it is used in amounts which correspond in activity to such doses of the ordinary galenical preparations of digitalis as commonly cause nausea and vomiting it does cause gastric disturbances quite as readily as the latter.

Among the clinicians who have found that Digalen causes gastric disturbances may be cited: Veiel,[34] Mueller,[35] Eichhorst[36] and Teichmann.[37]

Eggleston and Hatcher[38] compared the emetic and cardiac activity of Digalen and numerous other digitalis bodies and preparations and found that the emetic activity of Digalen was decidedly greater in proportion to its cardiac (or therapeutic) action than was that of digitalis or digitoxin.

In the absence of any evidence to controvert this clinical and experimental evidence, the continued claim that Digalen does not disturb the stomach must be looked on as deliberate mis­rep­re­sen­ta­tion.

MISLEADING THERAPEUTIC CLAIMS

The recommendation that Digalen be dismissed from N. N. R. is made with the full appreciation of the fact that the manufacturers of Digalen and their agents have repeatedly stated that they desired to comply with the rules of the Council, and that they have withdrawn several statements to which the Council has taken exception, but the fact remains that despite these reiterations the advertisements of Digalen continue to embody statements which the Council can only consider misleading.

The Council believes that the following advertisements constitute gross therapeutic exaggerations:

“Digalen a sheet anchor in pneumonia; a strong support to the heart in this deadliest of infectious diseases among adults. The prompt action of Digalen, by intravenous or intramuscular injection makes it possible to save lives which might be otherwise hopelessly lost. The best digitalis preparation which we have at the present time.”[39]

“The digitalis for children. Because its dosage can be controlled. Endorsed by pediatrists everywhere.”[40]

“The myocarditis of Tuberculosis so frequently encountered, especially in the advanced stage of the disease, may be controlled with the aid of Digalen. The standard digitalis preparation.”[41]

“Digalen is Absolutely Reliable. It is standardized and consequently always uniform. It does not produce gastric disturbances.”[42]

Digalen is not a sheet anchor in pneumonia, for there is no drug deserving such a title. Digalen has no action which other digitalis preparations lack, and cannot save lives otherwise hopelessly lost. The dosage of Digalen cannot be controlled any better than that of other digitalis preparations, since its activity is variable. We cannot control the myocarditis of advanced tuberculosis by this or any other means.

CLAIMED SUPERIORITY

Various digitalis principles, including digitoxin, digitalin (true) and digitalein, have been known for many years. Therapeutically they have been found wanting and there appears to be no basis for the continued claim that Digalen has any superiority over these several digitalis principles. On the contrary, the evidence is accumulating that Digalen has no advantage in any particular over a solution of digitalein, and misleading claims of the manufacturers and their agents certainly interfere with the formation of that calm and unbiased opinion on the part of the general practitioner, which, when applied to the non-proprietary digitalis principles has caused them to fall into disuse.​—(From The Journal A. M. A., Sept. 5, 1914.)

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