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

Chapter VIII: Part I: Council Reports (3)

Text size

“Recent Chemical Investigations of Cod Liver Oil show that the
active principles contain the nutritive qualities attributed to the
whole oil.”

The Council has previously expressed the opinion[19] that the preponderance of evidence indicates that whatever therapeutic value cod liver oil may have depends chiefly, if not entirely, on its fat (oil). There never was any evidence or scientific authority for the theory that the therapeutic value of cod liver oil was independent of its fat content. The fact that the fat is the growth-promoting element has already been shown, and J. P. Street, chemist for the Connecticut Agricultural Experiment Station (The Journal A. M. A., Feb. 20, 1915, p. 638), in a series of experiments on a number of the so-called extracts of cod liver or cod liver oil (including Hagee’s Cordial) has conclusively demonstrated that the growth-promoting properties of the oil are not to be found in the extracts. Street placed rats on a ration not sufficient to maintain normal nutrition and growth for an extended period. After the rats had been on this ration for some time and a failure to maintain weight was indicated, an amount of dealcoholized Hagee’s Cordial was substituted for a portion of the lard contained in the ration. Later Hagee’s Cordial was replaced by cod liver oil.

[19] The Journal A. M. A., Oct. 9, 1909, p. 1201.

Street says:

“None of the four rats did well on Hagee’s Cordial; in fact, they
lost 1.2 to 15.4 gm. during feeding periods of from seven to
fourteen days.”

“The rats failed so quickly when put on Hagee’s Cordial that in two
cases the animals did not recover even when put on the full cod
liver oil ration.”

“... the four rats during the Hagee period, instead of gaining the
normal 24 gm., actually lost 36.2 gm., while during the cod liver
oil period instead of gaining 114 gm., they gained 156.4 gm.”

“_The inferiority of Hagee’s Cordial as a reconstructive and a
nutrient compared with ordinary cod liver oil is apparent._”

Hagee’s Cordial of the Extract of Cod Liver Oil Compound has neither the nutritive qualities nor the reconstructive efficacy of cod liver oil. This mixture is worthless for the conditions for which it is advertised, and is marketed under misleading and unwarranted claims. It is recommended that Hagee’s Cordial be held ineligible for New and Nonofficial Remedies.--(_From The Journal A. M. A., April 10, 1915._)

WAMPOLE’S PERFECTED AND TASTELESS PREPARATION OF
AN EXTRACT OF COD LIVER[J]

Report of the Council on Pharmacy and Chemistry

[J] See also reports on Hagee’s Cordial preceding and Waterbury’s Compound following this; also The Comparative Nutrient Value of Cod Liver Oil and Cod Liver Oil Cordials, p. 442.

Wampole’s Preparation is another of the oil-free “extracts” of cod liver. The following formula (which, be it observed, is non-quantitative and therefore practically worthless) is published by the owners, Henry K. Wampole & Co., Inc.:

“Contains a solution of an extractive obtainable from fresh cod
livers, the oily or fatty portion being afterward eliminated. This
extractive is combined with Liquid Extract of Malt, Fluid Extract
of Wild Cherry and Compound Syrup of Hypophosphites (containing
Calcium, Sodium, Potassium, Iron, Manganese, Quinin and Strychnin).”

An alcohol content of 17 per cent. is declared on the label. The following claims are typical of those made for the preparation:

“This grease, or oil, is not present in Wampole’s Preparation
of the Extract, which is _palatable_ and, at the same time,
very efficient as a stimulant to the centers of nutrition and
assimilation. It is unsurpassed as a reconstructive tonic ...”

“[Cases] with a marked tendency to pulmonary troubles,... if a
timely impulse be given them will easily shake off the impending
evil. Wampole’s Preparation gives that timely impulse ...”

In the Council’s opinion, as previously expressed,[20] such therapeutic value as there may be in cod liver oil is chiefly, if not altogether, due to the fat (oil). Lately, the investigations of J. P. Street of the Connecticut Agricultural Experiment Station have definitely disproved the claims made for the Wampole’s and similar preparations. In Street’s experiments, rats were placed on a ration insufficient for normal nutrition and growth. After the rats had been on the ration for a time long enough for inability to maintain weight to become evident, dealcoholized Wampole preparation was substituted for a portion of the lard contained in the ration. Later the Wampole preparation was replaced by cod liver oil. From these experiments it appears that, although the Wampole preparation is said to contain malt extract and sugar, it does not show the advantage over ordinary cod liver oil as a source of nutriment which is claimed for it by the manufacturers. Street emphasizes that the Wampole preparation does not possess to any marked degree the reconstructive properties of cod liver oil, butter fat and egg yolk, on which foods rats gain weight rapidly and steadily after having been on a deficient diet. Street calls attention to the fact that the amount of alcohol consumed daily by the user of the Wampole preparation (the equivalent of 0.7 fluidounces of whiskey) explains to a considerable extent the asserted tonic virtues of the preparation.

[20] The Journal A. M. A., Oct. 9, 1909, p. 1201. (See following report, this volume.)

Though offered as an efficient substitute for cod liver oil, Wampole’s “Perfected and Tasteless Preparation of an Extract of Cod Liver” lacks both the nutritive and the reconstructive properties and is marketed under an indefinite name and unwarranted and untrue claims. It is recommended that Wampole’s Preparation be held ineligible for New and Nonofficial Remedies.--(_From The Journal A. M. A., April 10, 1915._)

WATERBURY’S METABOLIZED COD-LIVER OIL COMPOUND[K]

Report of the Council on Pharmacy and Chemistry and Laboratory
Contribution on Which It Is Based

[K] See also preceding reports on Hagee’s Cordial and Wampole’s Preparation; also Waterbury’s Compound once more, p. 291; The Comparative Nutrient Value of Cod Liver Oil and Cod Liver Oil Cordials, p. 422.

The following report has been adopted by the Council and its publication directed

W. A. Puckner, Secretary.

_To the Council_:--Your committee on pharmacology has read with interest the contribution from the Association’s laboratory on Waterbury’s Metabolized Cod-Liver Oil Compound. The report shows that misleading and false statements are made in regard to the composition of the product and also that exaggerated and unwarranted claims are made for its therapeutic value. In view of the attempt of the Waterbury Chemical Co. to create a false impression in regard to the therapeutic value of the composition of its product, it is recommended that the following report be adopted and published:

The Council believes that there is a preponderance of evidence to indicate that whatever therapeutic value cod-liver oil has, that value depends chiefly, if not entirely, on its fat (oil). In the opinion of the Council, the word cod-liver oil should not be used in connection with any preparation unless it consists to a large extent (25 per cent. or more) of cod-liver oil. Since Waterbury’s Metabolized Cod-Liver Oil Compound contains no appreciable quantity of cod-liver oil, the name is incorrect and misleading, and as a cod-liver oil preparation it is believed to be wholly valueless. The Council has previously voted that Waterbury’s Cod-Liver Oil Compound be refused recognition because of conflict with Rules 1 and 6.--(_From The Journal A. M. A., Oct. 9, 1909._)

[CONTRIBUTION FROM THE CHEMICAL LABORATORY OF THE AMERICAN MEDICAL ASSOCIATION]

Waterbury’s Metabolized Cod-Liver Oil Compound

W. A. Puckner and L. E. Warren

A full page advertisement of Waterbury’s Metabolized Cod-Liver Oil Compound appeared in the _Iowa Medical Journal_, March 15, 1909, in the form of a letter purporting to give the results of an analysis of the product made for the firm by a Chicago chemist. In this letter-advertisement the chemist states at the outset that the results of his examination “are somewhat at variance with the statements made in The Journal.” These statements he quotes as follows:

1. It is a clear liquid and no globules of oil are seen under the
microscope. It is therefore not an emulsion.

2. It is of acid reaction when mixed with water and remains clear
when strongly acidified. Hence it does not contain a soap, and is
not a saponification of fat.

3. It mixes with water without precipitation, hence, it can not
contain more than traces of a fatty acid.

The chemist admits in his letter to the firm that his analyses verify statements 1 and 3, but regarding statement 2 he says: “I find that your preparation is acid in reaction, but when strongly acidified gives a distinct turbidity within 10 minutes and a voluminous precipitate within 1 hour. This precipitate is shown to consist of fatty acids of cod-liver oil, which are thrown down by the splitting of the soaps, on acidifying either with sulphuric or hydrochloric acid.” From these results he states that to him it seems that the “preparation does not deserve the statement that it contains no soap, as there is no question whatever of the presence of cod-liver oil.”

While in the letter published in this advertisement the chemist claims to have demonstrated the presence in the product of “saponified cod-liver oil,” he _omits to mention the quantities_ of the soap present. In the article that originally appeared in The Journal (Oct. 13, 1906), in addition to the three paragraphs quoted by the chemist, the following statements were made:

“By these simple tests a physician is easily able to demonstrate that the preparation does not contain cod-liver oil. It is therefore valueless for the purpose of nutrition for which we give the oil. More careful analysis confirms the results of these tests and shows that it contains no fat or fatty acids (except the merest traces)....”

At the time these statements were published in The Journal, the _St. Paul Medical Journal_, October, 1906, contained an advertisement for Waterbury’s Metabolized Cod-Liver Oil Compound, which contained this statement:

“The only tasteless preparation on the market which contains
Cod-Liver Oil in its entirety. The metabolized product is obtained
by the action of digestive ferments on pure Cod-Liver Oil.”

In the _Ohio Medical Journal_ of Feb. 15, 1907, there appeared in the form of an advertisement what purported to be an analysis of Waterbury’s Metabolized Cod-Liver Oil Compound by Prof. C. N. Kinney of Drake University. While Professor Kinney made a quantitative analysis of the preparation, the quantities were omitted from the analysis as published. A footnote added by the Waterbury Chemical Company called attention to this fact and closed as follows:

“Any physician who is not satisfied with the analysis we will
be only too glad to furnish the complete analysis by our
representatives.”

If this weirdly constructed sentence meant anything, it meant that the complete analysis would be furnished on request. Such requests to the company, however, from various sources failed to elicit the information required nor was the “complete analysis” forthcoming. The inference to be drawn is fairly plain.

In a circular accompanying the product as sold at present, this statement occurs:

As previous examination disclosed only the merest traces of cod-liver oil in the product though claims were made that it “represents cod-liver oil in its entirety,” and in view of the fact, too, that present advertisements emphatically declare that cod-liver oil is present in the preparation as now sold, it was thought best to examine some of the preparation with especial reference to the quantities of fatty acids from cod-liver oil.

It is interesting in this connection to note that this product is no longer being sold under the name “Metabolized Cod Liver Oil Compound.” See the illustrations of the old and new labels.]

The results of the examination are briefly as follows: The total quantity of acids isolated amounted to about 0.3 per cent., and of this amount about two-thirds was _salicylic acid_. Thus it appears from the examination of the specimens bought on the open market that the preparation contains at most but 0.1 per cent. of the fatty acids from cod-liver oil, a totally insignificant quantity.

Notwithstanding the protestations by the manufacturers, in the form of published analyses and circulars, it is seen that the statements published in The Journal, Oct. 13, 1906, p. 1207, are essentially substantiated; it is further evident that the product does not deserve to be designated as a cod-liver oil preparation. To obtain a medicinal dose of cod-liver oil the patient would be compelled to swallow the contents of a bottle of this mixture, and as the product contains 11 per cent. alcohol the patient who did so would probably experience a degree of exhilaration not referable to cod-liver oil.--(_From The Journal A. M. A., Oct. 9, 1909._)

Declared Misbranded

This product of the Waterbury Chemical Company, of Des Moines, Iowa, was exposed in The Journal of the American Medical Association, October 9, 1909. In May, 1910, the United States Government issued a notice of judgment in which it was declared that Waterbury’s Metabolized Cod Liver Oil Compound was misbranded. The court rendered its decree of condemnation and forfeiture.--[_Notice of Judgment, No. 303._]

WATERBURY’S COMPOUND

Report of the Council on Pharmacy and Chemistry

The Waterbury Chemical Company having requested that the Council reconsider its action of four years ago (see preceding report) on the product then known as Waterbury’s Cod-Liver Oil Compound, now called Waterbury’s Compound, the matter was submitted to a referee. The referee reported that the statement now made as to the composition of this product is as follows:

“Made from Cod Liver Oil, Digestive Ferments, Malt Extract
Unfermented, Hypophosphites Comp. Special, Ext. Cherry, Eucalyptus,
Aromatics, etc.”

He held that the Waterbury Chemical Company has not submitted satisfactory evidence to indicate that the objections of the Council’s former unfavorable report have been met; that there is no evidence that the product is a substitute for cod-liver oil in any way; and that under the present methods of exploitation it constitutes what is at least an inferential fraud; and recommended that no further consideration be given to Waterbury’s Compound. The report was adopted by the Council.--(_From The Journal A. M. A., March 20, 1915._)

COLCHI-SAL

Report of the Council on Pharmacy and Chemistry

Colchi-Sal, said to be made by the Anglo-American Pharmaceutical Co., Ltd., New York, is advertised, sold and “guaranteed” (sic) by E. Fougera and Co., Inc., New York. According to the label of a recently purchased specimen:

“Each Capsule contains Cannabis Indica (Active Principle of)
1-500th Grain (1/8 Milligram); Colchicine (Crystallized) 1-250th
Grain (1/4 Milligram); Methyl Salicylate 20 Centigrams.”

The advertising circular around the bottle adds that the mixture also contains “appropriate aromatic adjuvants.”

It is recommended in “Gouty and Chronic Rheumatic Manifestations,” “acute cases of Gout,” “intestinal auto-intoxication or dyspepsia,” “bilious headaches,” etc. Salicylates are generally recognized as valuable in acute manifestations of acute articular rheumatism; colchicum is useless in these conditions. Both salicylates and colchicum are practically useless in chronic rheumatic and in chronic gouty affections. For dyspepsia, bilious headache, etc., salicylates are distinctly contra-indicated and the drastic purgation produced by colchicum would not be thought desirable. Though methyl salicylate administered internally is not generally considered so efficient as sodium salicylate, it is asserted that the former

“... is found far more effective than salicylate of soda or other
salicylic derivatives when given in conjunction with colchicine as
Colchi-Sal.”

Further, the highly improbable and unsubstantiated claim is made that “the active principle of _Cannabis indica_” (whatever that may be) “corrects any tendency of the colchicine to irritate the gastro-intestinal tract” and that the “appropriate aromatic adjuvants” “prevent intolerance of the methyl salicylate.”

Colchi-Sal is put up in a way to appeal to the public; the bottle has the name “Colchi-Sal” blown in the glass; the label gives full instruction for the use of Colchi-Sal, and also the price, suggesting that the preparation may be freely purchased. Wrapped around the bottle is a circular advising its use in various affections.

The physician who acts on the advice that it is well to “insist on the pharmacist dispensing original bottles ...” of the “little green capsules” actually suggests to his patient the use of this preparation of methyl salicylate and colchicum in conditions in which these drugs may do much harm and in which proper treatment is imperative.

Colchi-Sal is typical of unscientific ready-to-take proprietaries. It was held ineligible for New and Nonofficial Remedies because of its secret composition, viz., the unknown nature of the “active principle of Cannabis indica” (Rule 1); because the circular in the package and the name blown in the bottle constitute advertisement to the laity (Rule 4); because the claim that cannabis indica removes the gastro-intestinal irritation, and the claim of the superiority of methyl salicylate are unwarranted therapeutic claims (Rule 6); because the name does not indicate the presence of the habit-forming cannabis indica, and because of its unscientific composition (Rule 10).--(_From The Journal A. M. A., March 20, 1915._)

CYPRIDOL CAPSULES

Report of the Council on Pharmacy and Chemistry

Having voted that Cypridol Capsules be refused recognition, the Council directed that for the information of physicians publication of the following report be authorized.

W. A. Puckner, Secretary.

Cypridol Capsules, sold by E. Fougera & Co., New York, are stated to be “Bottled in the New York Laboratories of Vial, late Rigaud and Chapoteaut, Paris,” and to contain, in each capsule, 2 mg. (1/32 grain) mercuric iodid (biniodid of mercury) dissolved in a fatty oil. They are claimed to permit the administration of mercury without danger of salivation--an obvious misrepresentation.[21] Cypridol Capsules are marketed in a way to appeal to the public. If they are once prescribed, the directions on the bottle and the full instructions for the treatment of syphilis by means of Cypridol and by other proprietaries sold by Fougera & Co. is likely to lead the patient to attempt the treatment of this malady on his own accord, and thus probably to forfeit his chances of cure. Cypridol is a vicious example of the “ready-to-take” proprietaries.

[21] Physicians who desire to use a solution of mercuric iodid in oil should direct their pharmacist to prepare it according to the method suggested by Lemaire (Repert. pharm., xxi, 97-102, from Chem. Abst., 1909, p. 1444), viz.: One gm. of mercuric iodid is dissolved in 50 c.c. sterilized castor oil by warming to about 70 degrees, 3 gm. guaiacol are added and the solution made up to 100 c.c. with sterilized poppy oil. Or according to a later suggestion (Dunning: Proc. Am. Pharm. Assn., 1910, p. 1123): one gm. of mercuric iodid is dissolved in 99 gm. of a mixture of equal parts of sterilized castor and olive oils, by warming on the water-bath.

Cypridol Capsules are in conflict with the rules of the Council as follows:

Rule 4: The dosage, price, etc., on the label, and the name “Cypridol” blown in the bottle, all tend to a direct self-prescribing by the public. In addition to the objectionable statements on the bottle itself, the preparation is put up in patent medicine style and is accompanied by a circular giving full directions for the use of this and of other proprietaries for the treatment of syphilis in all of its stages. The circular states that “a 1 per cent. solution of bin-iodide of mercury in an aseptic oil” is “An Improved Specific in the Treatment of Syphilis,” and after lauding the virtues of Cypridol, gives full directions for the treatment of syphilis in its various stages by means of Capsules of Cypridol augmented, during periodical cessation of treatment, by “small doses of iodide of strontium (Paraf-Javal’s standard solution, thirty grains to the ounce).” Further, the circular expounds the need of “a toning up of the general system” and by means of obsolete theories and obviously untrue assertions recommends “_Chapoteaut’s Wine_ [another of their proprietary preparations], each ounce of which contains 10 grains of phospho-glycerate of lime. This is a delicious, nutritive tonic. A pint bottle costs $1.00.”

Rule 6: Whereas it is evident that Cypridol, depending for its effects on mercuric iodid, the ordinary well-known hydrargyri iodidum rubrum of the U. S. Pharmacopeia, must naturally have the properties of a mercuric compound, unwarranted claims such as the following are made:

“CYPRIDOL does not render patients anemic. Ptyalism never follows
the administration of the capsules or injections. On the contrary,
patients rapidly put on flesh and keep well. There are no
diarrhoeas or other symptoms of intolerance even when the dose is
pushed.”

Rule 8: The non-informing name “Cypridol” for a mercuric iodid preparation is bound to lead to its use without consideration of the fact that a potent mercury preparation is being used, requiring a careful adjustment of dosage, a consideration of the needs of the individual case, a correct diagnosis, etc. While the advertising propaganda argues that “physicians recognize the advantage of prescribing this solution of mercuric iodide in an aseptic oil under the name of ‘Cypridol,’ because it does not betray to the laity the fact that mercury is being used,” not only the physician but also the patient has a right to know, and ought to know, the potent character of the remedy which is being administered.

It is recommended that Cypridol be refused recognition and that publication of this report be authorized.--(_From The Journal A. M. A., Dec. 19, 1914._)

CYSTOGEN, CYSTOGEN APERIENT AND CYSTOGEN-LITHIA[L]

Abstract of Report of the Council on Pharmacy and Chemistry

[L] For the unabridged report of the Council’s action on Cystogen, Cystogen Aperient and Cystogen-Lithia, see Reports Council Pharm. and Chem., 1914, p. 66.

Cystogen is the therapeutically suggestive name applied to hexamethylenamin by the Cystogen Chemical Company. While investigation has shown that hexamethylenamin yields formaldehyd only in the presence of an acid and consequently can produce an antiseptic effect only in the gastric juice and in the urine, it is claimed that Cystogen is an “intestinal antiseptic” and that it “bears its disinfectant and antitoxic qualities into well-nigh every important bodily cavity.”

As the sale of a simple drug even with the aid of the most extravagant claims probably did not offer sufficient opportunity for an extensive proprietary propaganda, the Cystogen Company has put out two other preparations, Cystogen Aperient and Cystogen-Lithia, and finds it an easy matter by means of extravagant claims, unwarranted assertions and pseudo-scientific arguments to recommend the use of one or another, or often all three, in a well-nigh endless number of diseases.

As the continued patronage of the medical profession cannot be relied on for proprietaries of this sort, the Cystogen Chemical Company takes good care that every Cystogen prescription is likely to spread the Cystogen gospel among the people. The Council has directed publication of its report on the Cystogen products to call attention to the way in which a simple drug of established value may be made the basis of an extensive proprietary propaganda. A conservative discussion of the action of hexamethylenamin appears in the Council’s publication, “Useful Drugs.” The Council therefore refused recognition to Cystogen, Cystogen Aperient and Cystogen-Lithia.--(_From The Journal A. M. A., Dec. 12, 1914._)

CYSTO-SEDATIVE

Report of the Council on Pharmacy and Chemistry

Cysto-Sedative is sold by Strong, Cobb and Company, Cleveland, Ohio, with the claim:

“Each fluid ounce represents:
Thuja Occidentalis, 3-1/2 grains.
Pichi, 18 grs.
Saw Palmetto berries, 36 grs.
Triticum Repens, 36 grs.
Hyoscyamus 8 grs.
All inert extractive matter being eliminated.”

The therapeutically active constituents of arbor vitæ, pichi, saw palmetto and couch grass have never been isolated--indeed, it has not been proved that all of these drugs contain any therapeutically active constituents. Yet the absurd claims are made that all inert matter has been eliminated and each lot of drug used in the preparation of Cysto-Sedative is “tested in reference to its medicinal activity.” Equally preposterous is the claim:

“In formulating Cysto-Sedative each drug entering into its
composition was subjected to careful study clinically to determine
the exact proportion required when combined to increase their
efficiency as a whole. Cysto-Sedative is scientifically prepared,
the proportion of each individual drug being so finely adjusted as
to increase their therapeutic action in the conditions for which
they are intended, forming a preparation always reliable and of the
very highest medicinal activity.”

Some other extravagant claims made for this complex unscientific mixture are:

“It gives relief in almost every form of cystitis and
prostatitis....”

“The best results are obtained in the worst chronic cases of
cystitis and prostatitis....”

“In Cystitis, Urethritis, Prostatitis, Inflammation of the Vesicle
Neck, complicated with Gonorrhoea, Enuresis, Painful Micturition,
the action of Cysto-Sedative is prompt.”

The Council voted that Cysto-Sedative be refused recognition.--(_From The Journal A. M. A., Dec. 12, 1914._)

TAKA-DIASTASE AND LIQUID TAKA-DIASTASE

Report of the Council on Pharmacy and Chemistry

Some time ago it was decided that a reexamination should be made of Taka-Diastase and Liquid Taka-Diastase, both of which had previously been rejected, to ascertain whether or not the preparations were in accord with the claims made for them by the manufacturers. Accordingly, the matter was referred to a committee of the Council, and an examination of specimens of these two preparations bought in the market was made. The referee’s report, which appears below, according to the usual procedure, and before final confirmation by the Council, was first submitted to the manufacturers of Taka-Diastase for comment. The report recommends that the rejection of Taka-Diastase and Liquid Taka-Diastase be allowed to stand, and that the report be published. Parke, Davis & Co., in their reply, which is given in full below, claim that the report is unjust concerning Liquid Taka-Diastase, because the period of activity of the preparation has been greatly prolonged by reducing the amount of alcohol from 18 per cent. to 10 per cent. and by adding glycerin. They reiterate their claims for the digestive power of Taka-Diastase, but admit that it will not reduce the stated amount of starch to the colorless end-point in ten minutes (the standard method for the valuation of diastase). They further state that they would change the word “digest” on the label to “liquefy.”

The conclusion of the report having been questioned, the entire matter was referred to a member of the Council’s staff of clinical consultants. His report, which, also, is given in full below, states that the material before him was sufficient to decide the matter, and no further tests were necessary. He concludes that the claims of the manufacturers regarding the strength and properties of the material are erroneous and exaggerated; that the literature still sent out by Parke, Davis & Co. is misleading; and that if substitution of the word “liquefy” for “digest” were endorsed by the Council confusion would result which would give an exaggerated and false value to Taka-Diastase. He therefore recommends that the report of the reinvestigation of Taka-Diastase be accepted by the Council and published.

This report of the second referee was referred to Parke, Davis & Co. with the request that they state more definitely the actual amylolytic strength of their preparations. To this they replied that they had no desire to discuss the subject further, or to make any additional statements.

In accordance with the second referee’s recommendations, the Council confirmed its provisional action and voted that the rejection of Taka-Diastase and Liquid Taka-Diastase be allowed to stand, and that the report which appears below be authorized for publication.

W. A. Puckner, Secretary.

_REFEREE’S REPORT ON TAKA-DIASTASE AND LIQUID TAKA-DIASTASE_

Following is the report of the committee to which was referred the reexamination of Taka-Diastase and Liquid Taka-Diastase:

Some time ago a comparison was made of the various methods proposed for the valuation of preparations claimed to have amylolytic power. This work was reported in The Journal,[22] and the method proposed for the testing of diastase preparations now appears in New and Nonofficial Remedies.[23] In view of the incorrect and exaggerated claims made for Taka-Diastase, the Council in 1908 was obliged to rescind its acceptance and to direct its omission from New and Nonofficial Remedies. The report contained the following reference to Taka-Diastase (Parke, Davis & Company), a product that had been accepted for inclusion with New and Nonofficial Remedies:

[22] The Journal A. M. A., July 11, 1908, p. 140.

[23] New and Nonofficial Remedies, 1912, p. 68; The Journal A. M. A., April 15, 1911, Part 2, p. 18.

“The widest discrepancy between the values as claimed by the
manufacturer and those found by actual tests seems to be shown in
the case of Taka-Diastase. The liquid preparation has been tested a
number of times in different samples and has always been found weak.
Some samples, in fact, were quite inert. This ferment appears to lose
strength very rapidly in solution, as the manufacturers now concede.
The stability of the solid product is also far from satisfactory, and
appears to be less than that of the ferment as marketed some years
ago. The two samples examined recently were weak.”

More than three years have now elapsed since the publication of the Council’s findings regarding Taka-Diastase--sufficient time, it is believed, for the manufacturers to modify either their claims or the product itself, and thus again make it eligible for inclusion with New and Nonofficial Remedies. With this idea in mind new specimens of Taka-Diastase and Liquid Taka-Diastase were purchased from a Chicago drug house and the preparations reinvestigated. The following is the report of this reinvestigation.

REPORT OF THE REEXAMINATION

In our report on the diastase preparations three years ago, it was
recommended that Taka-Diastase be removed from New and Nonofficial
Remedies, because the examinations showed that it did not have
the digestive strength claimed for it. This was true both for
Taka-Diastase itself and for Liquid Taka-Diastase. So far as the
latter was concerned, the starch-converting power was practically
_nil_ in those preparations which had been in the drug stores for
some months.

During the last few weeks new tests have been carried out with
several samples of the Taka-Diastase preparations and the results
obtained are essentially the same as those obtained in the former
examinations. The liquid preparation is still extremely weak in
starch-converting power, while we found that Taka-Diastase itself
would convert only 16.6 parts of pure anhydrous starch to the
colorless end-point in ten minutes, as explained below.

In our method of experimentation we determine the weight of the
diastase in question which will convert a given weight of starch in
uniform paste to the so-called colorless end-point in ten minutes,
that is to the point where it will no longer give any color reaction
with a standard iodin solution. The standard starch weight in 50 c.c.
always is 1 gm. or 1,000 mg. and to a series of flasks containing
this amount of starch, maintained at a constant temperature of 40 C.,
the diastase dilutions are added. These diastase dilutions are made
by dissolving small, accurately weighed amounts of the sample in
some small, constant volume of water, usually 5 or 10 c.c. and they
are then poured into the starch flasks at the right temperature, and
agitated regularly.

Tests are made by taking a few drops from each flask and mixing
with the iodin solution. The end-point is reached when a dilution
is found which, at ten minutes from the mixing time, gives no color
with the iodin reagent. The first set of tests is taken as a general
guide, and quite accurate results may be obtained in a second set of
dilutions.

We first used a sample of Taka-Diastase bought in the open market. It
was found that 140 mg. were required to convert the gram of starch as
explained. This is equivalent to a conversion of 7.14 parts of starch
by 1 part of the Taka-Diastase.

A new, and possibly fresher, sample was then obtained and the
test repeated. With this new sample it was found that 60 mg. were
necessary to convert the gram of starch to the colorless end-point
in ten minutes, from which it follows that 1 part of the ferment
will convert 16.6 parts of starch to the colorless end-point in
the same time. With a new sample of Liquid Taka-Diastase obtained
simultaneously it was found that 3.5 c.c. were necessary to convert
1 gram of starch to the colorless end-point in ten minutes. As a
fluidounce of this liquid is said to contain 20 grains of the solid
it will be seen that the results approximately agree with those of
the first sample of the solid, and that they are both very low.

In the earlier tests 16 parts of starch converted by 1 part of the
ferment was the value found. These results are in close agreement
with values reported by Sherman (_Jour. Am. Chem. Soc._, xxxii, 1073)
for a sample of recent purchase. He found a conversion of 51 parts of
starch to the colorless end-point in _thirty_ minutes for one sample,
while for another he found 66 parts, in the same time. It will be
noted that our time limit is _ten_ minutes. It is worthy of note
that for a perfectly fresh and specially prepared sample furnished
by Dr. Takamine, a conversion of 278 parts in _thirty_ minutes was
found by Sherman. Taking the time into consideration, it will be seen
that the results are about the same for the market samples as those
found by us and much lower than claimed, as well as much lower than
for other makes of similar products. The difference in the behavior
of fresh specially prepared Taka-Diastase and the market sample is
very clearly shown. No one questions the fact that fresh laboratory
samples of Taka-Diastase may show a moderate converting power on
starch. But we have to deal with the _activity of market samples
only_, and Sherman’s work and our own show the low digesting power of
the product as physicians may secure it on the market.

The marked difference in activity between perfectly fresh and
ordinary market samples of Taka-Diastase is very clearly shown also
in a recent paper published by Wohlgemuth.[24] In the digestion
of starch paste to the “dextrin” stage Wohlgemuth found in the
commercial sample a strength approximately a hundred times less than
that observed in a fresh sample sent him by Dr. Takamine.

[24] Wohlgemuth: Biochem. Ztschr., March 18, 1912.

Wohlgemuth’s results were obtained by a method not essentially
different from ours, with this difference, however, that he digested
through 24 hours in the cases reported, and carried the reaction
to the “dextrin” stage only, in place of to a colorless end-point.
Making the proper reductions, it is evident that the actual values
found by him for the market samples bought in Germany are not greater
than those reported by us.

The reference to the work of Sherman is made because, in a following
paper in the same journal, he recommends the use of salt as an
activator in finding the strength of certain diastase preparations.
It is well known that dialyzed diastase preparations and starch of
highest purity have but slight action on each other; a little salt
increases the activity greatly, and also increases the activity of
commercial diastase preparations. These facts Sherman utilizes in
working out a method for valuation of commercial diastases. The facts
were well known to us at the time of our former report, but it was
not thought best to depart from the general method which had been
in use by all analysts following the general scheme of Roberts.
Quite recently, I. Bang has published a paper on the investigation
of diastase (_Biochem. Ztschr._, xxxii, 417) in which he studies the
behavior of sodium chlorid and other salts on the rapidity of starch
conversion, and finds that a much smaller amount of salt than Sherman
recommends brings the maximum increase.

The method employed in our former tests is a good comparative method,
and this is all that may be claimed at present for any method. By
adding salt to our starch solution the activity of Panase and other
ferments is likewise greatly increased. For Panase, a preparation
possessing rather high starch-converting power, we have recently
found an increase of about 30 per cent. in the converting power,
with salt present. Working to loss of blue color, merely, it is
possible in this way to get a higher value than that claimed by the
manufacturer. There is no practical gain in using the salt for our
purpose as the methods are at best arbitrary, and the results only
comparative.

Taking all the facts into consideration, it is recommended that the
rejection of Taka-Diastase and Liquid Taka-Diastase be allowed to
stand and that, in view of their extensive exploitation, this report
be authorized for publication so that physicians may know the facts.

This report was referred to Parke, Davis & Co., and they made the following reply:

“The report submitted in your letter of the 23d is, we contend,
erroneous and unjust: first, to our Liquid Taka-Diastase, because
over three years ago we changed our formula, reducing the alcohol
from 18 per cent. to 10 per cent., increasing the glycerin and thus
prolonging greatly the period of activity.

“As for our regular Taka-Diastase, our claim is and has been for
years simply that Taka-Diastase will digest or hydrolyze 150 times
its weight of starch in ten minutes, under proper conditions. We
do not claim, we do not permit our representatives to claim, that
Taka-Diastase will completely transform starch, to the colorless
end-point, into sugars. Taka-Diastase is used to supplement a
deficiency of ptyalin and converts the starch into soluble material
with great rapidity, thus giving the gastric fluid immediate access
to the proteids.

“If in the enclosed labels the word ‘digest’ were replaced with the
word ‘liquefy,’ the claim could not be assailed by the most carping
critic. To save any possible question, we shall therefore make this
change in our label, having it read: ‘Taka-Diastase will liquefy 150
times its weight of starch in ten minutes, under proper conditions.’
Is there the slightest question in your mind that this statement as
just quoted is entirely correct and entirely supported by clinical
experience?

“It is our conviction that Taka-Diastase has a very remarkable power
to hydrolyze starch either in the test-tube or in the stomach, and
that this property is of great utility in clinical work. We do not
claim that its conversion of the starch into sugars is complete, to
the colorless end-point of the Johnson test; and on this point we
have been perfectly frank with the Council, as well as with every
physician who has taken sufficient interest to inquire.”

In view of the above protest, the matter was submitted to a second referee, who reported as follows:

“Your referee on the matter of Taka-Diastase has made a careful
investigation of the reports and correspondence submitted, and begs
to make the following report:

“The question at issue, viz., whether Taka-Diastase should be
included in New and Nonofficial Remedies, I believe, can be
determined by the material before me, and further tests of the
material are not necessary.

“The letter of the makers of Taka-Diastase admits that the early
claims regarding the strength and properties of the material were
erroneous and exaggerated. Since the product was once admitted to New
and Nonofficial Remedies, it may be claimed that as the Council on
Pharmacy and Chemistry must have been in error then, it may be now.
Your referee does not consider this supposition worth discussing. The
conclusion he draws is that the Council was too hasty in accepting
the preparation, and that the incident shows how much better it would
be in all cases to accept no remedy until sufficient time has been
given for conclusive tests.

“The literature still sent out by Parke, Davis & Co. regarding
Taka-Diastase is misleading and of a kind more appropriate for a
nostrum than a standard chemical substance. What would we think if
morphin, quinin or even heroin were advertised in the same way? I
cite the statement, ‘Taka-Diastase digests starchy food with vigor
and directness.’ It seems to the referee that the proposition to
modify the label to indicate the amount of starch which is liquefied
rather than the amount which is saccharified, in accordance with the
Council’s standard, is bound to lead to confusion and to give an
exaggerated and false value to Taka-Diastase.

“Your referee recommends that the report of the reinvestigation of
Taka-Diastase which has been submitted to me, be made available to
the medical profession, and that the rejection of Taka-Diastase and
Liquid Taka-Diastase be allowed to stand.”

This report of the second referee was submitted to Parke, Davis & Co., with the request that they state more explicitly their claims regarding the activity of Taka-Diastase and Liquid Taka-Diastase, in order that, if they decided to revise their claims for the preparations, such revision of claims might be published along with the reports of the Council. They replied:

“Answering your note of the 15th instant: We have no desire to
discuss further the subject of your letter of February 24, or to make
any statement beyond that set forth in our letter to you of Dec. 27,
1911.”--(_From The Journal A. M. A., July 6, 1912._)

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.

[25] The Journal A. M. A., Sept. 11, 1909, p. 869.

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.

[26] These reports (A, first report on Digalen and B, examination of Digalen Tablets) will be published in the 1914 Annual Council Reports. A reprint of the entire matter dealing with the rejection of Digalen will be sent on receipt of a two-cent stamp.

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:

[27] The Journal A. M. A., Sept. 11, 1909, p. 869.

“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.

[28] Cloetta: München. med. Wchnschr., 1904, No. 33.

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]

[29] Kiliani: München. med. Wchnschr., 1907, p. 886.

[30] Kiliani: Am. Jour. Pharm., 1913, lxxxv, 224.

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.

[31] Clinical Suggestions and Reports, December, 1912, p. 24.

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).

[M] Owing to lack of space a portion of the report is here omitted. A detailed discussion of these results is included in the full report contained in the reprint.

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_.”

[32] Advertisement Brit. Med. Jour., April 26, 1913.

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.

[33] Hale: Hyg. Lab. Bull., 74.

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]

[34] Veiel: München. med. Wchnschr., 1906, liii, 2140.

[35] Mueller: München. med. Wchnschr., 1909, lvi, 904.

[36] Eichhorst: Deutsch. med. Wchnschr., 1905, xxxi, 49.

Previous Next

Comments

The Propaganda for Reform in Proprietary Medicines, Vol. 1 of 2Chapter VIII: Part I: Council Reports (3)

0%36 min left in chapter