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

Chapter X: Introduction: The Council on Pharmacy and Chemistry was established (3)

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They maintain that Formamint is not only absolutely harmless, but actually beneficial to the tissues. It may be used “to tone up and strengthen the tissues, prevent hoarseness, and allay irritation in singers, public speakers,” etc.

The claims urged as to its germicidal power are indeed glittering. This “new chemical compound” is claimed to liberate formaldehyd in some new and peculiar condition which, while it has a soothing and tonic effect on the cells of the human tissues, can at the same time quickly kill any form of bacterial life.

“Dissolving readily, it releases its germicidal, antiseptic
qualities, which impregnate the saliva and are carried naturally
and easily around the mouth and in the deepest crevices of the
throat--destroying the germs where they are causing the mischief.
Formamint prevents and destroys infectious germ life in a soothing
grateful way.”

“In the saliva it frees a germicide, fatal to germs but harmless
to the most delicate membranes. And flowing into every tiny corner
of the gums, tonsils and throat, into places where no gargle ever
reaches, it most effectively _disinfects_ the throat.”

The claims as to the preventive and curative effects of the preparation cover a large portion of the category of human ailments and distresses. The following quotations indicate some of its supposed properties:

“... it is therefore self-evident that Formamint should be
looked upon as a necessary part of the treatment of all forms of
tonsillitis.”

“The value of Formamint is equally great in diphtheric tonsillitis,
or as a prophylactic ...”

“The extraordinary success which I had with Formamint in a
school epidemic of scarlet fever during May and June, 1907, was
the determining factor which induced me to abandon the use of
inhalations, gargles, local applications in the treatment of
diseases of the throat, and to use Formamint exclusively for the
future.”

“There are naturally many similar conditions in which Formamint
may be used as a prophylactic, notably scarlet fever, mumps,
streptococcal and staphylococcal sore throats, ‘milk outbreaks’ of
sore throat, drain throats, hospital throats, and the like.”

“Formamint Tablets are indicated in Angina, Tonsillitis,
Pharyngitis, Stomatitis, Gingivitis, Glossitis, ulceration, spongy
or bleeding gums, Pyorrhea Alveolaris, ‘Smoker’s Sore Throat,’
Abscess or Boils, etc.”

“As a _Prophylactic_ against Diphtheria, Scarlet Fever,
Influenza, Measles, Epidemic poliomyelitis, and other pathogenic
micro-organisms. To neutralize putrefaction products in and about
the teeth, correct fermentative processes, deodorize and purify the
breath, etc.”

“To _tone up_, and _strengthen_ the tissues, prevent _hoarseness_
and _allay irritation_ in singers, public speakers, neutralize the
effects of dust-infection or _disinfect the saliva or sputum_ in
Influenza, Tuberculosis, etc.”

One man declares that along with specific constitutional treatment he “had the best results from the use of Formamint tablets” in a case of syphilitic ulceration of the tongue.

In short, Formamint is recommended for the treatment or prevention of almost everything, from a bad breath to such grave conditions as scarlet fever, diphtheria and tuberculosis, conditions in which a delay in proper treatment--for instance, in diphtheria, a failure to administer antitoxin--may result in the death of the patient.

A series of investigations was therefore undertaken in order to discover whether the extravagant claims regarding the germicidal power of Formamint could be verified.

Experimental Data

Two fifty-cent bottles of Wulfing’s Formamint were purchased in the open market and were kept well stoppered to prevent deterioration.

Qualitative tests showed the presence of formaldehyd and the amount was determined quantitatively by the hydrogen peroxid method as given by Sutton.[23] The results were respectively, 1.99 per cent. and 2.03 per cent. of formaldehyd.

[23] Sutton: Volumetric Analysis, Edition 10, p. 390.

Some determinations were made of the germicidal power of Formamint in vitro, that is, under controlled laboratory conditions. A twenty-four-hour plain agar culture of _Staphylococcus aureus_ was washed off in 10 c.c. of sterile 0.85 per cent. sodium chlorid solution. A 1:100,000 dilution of this was made in each of three flasks containing 100 c.c. of sterile saliva. Flask 1 contained 1 per cent. of Formamint, Flask 2, 5 per cent.; Flask 3, containing no Formamint, was kept as a control. At intervals samples were removed and dilutions made and plated in duplicate on standard agar. The plates were incubated twenty-four hours at 37 C., and plates containing less than 200 colonies were counted. The results are given in Table 1. After seven days there was no appreciable difference in the plates.

Another test was made by adding a 1 per cent. Formamint solution to plain agar plates inoculated with _B. coli_. A twenty-four-hour plain agar culture of _B. coli_ was washed off in 10 c.c. of sterile 0.85 per cent. sodium chlorid solution. A 1:1,000,000 dilution was made of this and 1 c.c. added to each plate. Varying amounts of 1 per cent. solution of Formamint were added to each plate. They were incubated seventy-two hours at 37 C. After seven days’ incubation the count was the same. The results are given in Table 2.

Another experiment was made thus: One loopful of a twenty-four-hour plain agar culture of _Streptococcus lacticus_ was mixed with a tube of North medium. One loopful from the inoculated tube was mixed with a second tube of North medium. Both tubes were poured into Petri dishes and allowed to cool. One half of each plate was well smeared with a 10 per cent. solution of Formamint in saliva. After twenty-four hours’ incubation at 37 C., only a few colonies appeared on the side to which the Formamint had been applied, while the other half was thickly covered with colonies.

TABLE 1.--SHOWING TIME IN WHICH CULTURES OF STAPHYLOCOCCUS AUREUS WERE KILLED BY DIFFERENT AMOUNTS OF FORMAMINT

===================+=================+=============+=================
Amount of Formamint| Period of |Average Count| Count on Flask
in Saliva |Standing at 37 C.| When Plated |of Saliva Without
(Per Cent.) | (Hours) | | Formamint
-------------------+-----------------+-------------+-----------------
1 | 3 | 32 | 3200
1 | 6 | 0 | 7000
5 | 1 | Few | 5000
5 | 2 | 0 | 4100
5 | 3 | 0 | 3200*
5 | 6 | 0 | 7000*
-------------------+-----------------+-------------+-----------------

* The last two observations were made at the same time as on the 1 per cent. solutions.

This work so far corroborates that reported in the literature quoted by the manufacturers. But the fact that a compound is a germicide when brought into intimate contact with bacteria in a solution or medium in a test tube or flask does not prove that it will be effective when used in the human throat.

THE ALLEGED GERMICIDAL ACTION

An attempt was made to discover whether or not the claims advanced by the manufacturers as to the perfect germicidal action of Formamint in all the nooks and crannies of the mouth and throat could be confirmed.

TABLE 2.--COUNT OF B. COLI CULTURES WITH DIFFERENT AMOUNTS OF FORMAMINT

======================================================================
No. c.c. of 1 per cent. Formamint 0 0.1 0.3 0.5 0.7 1.0 1.5 2.0 3.0
Count 160 33 39 26 15 12 2 0 0
----------------------------------------------------------------------

The first step in attacking this problem was to make comparative counts of the number of bacteria in the throat before and after the use of Formamint. The methods employed were as follows: The throat was gargled with 50 c.c. of sterile 0.85 per cent. sodium chlorid solution. In each case the same length of time, as far as possible, was used in the process. The liquid was collected in a sterile flask. The gargling in a series of experiments was begun not less than two hours after a meal. After some preliminary work the following dilutions of the 50 c.c. of salt solution were found sufficient: 1:1,000, 1:10,000 and 1:100,000. Plates were made in duplicate from each dilution and incubated seventy-two hours at 37 C. The counts were made on plates containing less than 200 colonies. Except where otherwise noted standard agar was used. The mediums were always prepared in the same way.

All the work was carried out under conditions as nearly natural as possible. The Formamint was taken according to the directions accompanying the trade package. Every opportunity was given the Formamint to penetrate all the crypts and recesses about the mouth and throat. The tablet was allowed to dissolve as slowly as possible, the time usually being five to six minutes, and saliva was thoroughly forced around the mouth before being swallowed. Plating was always done immediately after gargling so that no growth could occur in the salt solution. The results are given in Table 3. The numbers are average counts from several plates and calculated to show the number of bacteria washed out by the 50 c.c. of salt solution.

TABLE 3.--SHOWING THAT FORMAMINT DOES NOT GREATLY DECREASE THE NUMBER OF BACTERIA IN THE THROAT

Finally a determination was made of the number of streptococci in the throat before and after the use of Formamint. The throat was gargled in the manner previously described. The streptococcus count was made by the dilution method as given by Heinemann.[24] Culture tubes were used instead of fermentation tubes. One per cent. dextrose broth was the medium employed. One cubic centimeter was added to each of a series of ten tubes for each dilution and the following dilutions were used: 1:10,000, 1:100,000 and 1:1,000,000.

[24] Heinemann: Laboratory Guide in Bacteriology, p. 86.

The results given in Table 4 are the average count from a number of dilutions and are reported as the total number washed out by the 50 c.c. of salt solution.

TABLE 4.--SHOWING THAT FORMAMINT FAILS TO REDUCE THE NUMBER OF STREPTOCOCCI IN THE THROAT

Discussion

The contention that Formamint contains formaldehyd was confirmed by analysis.

The manufacturers also maintain that Formamint is a new, definite chemical compound, consisting of five molecules of formaldehyd and one molecule of lactose, and that when dissolved in the saliva the formaldehyd is liberated in some new and peculiar form, which they call nascent formaldehyd. This new kind of formaldehyd is, according to the advertising literature, especially powerful in its germicidal properties and at the same time has absolutely no irritating or harmful effects.

NOT A CHEMICAL COMPOUND

Thoms,[25] retained as an expert by the German government, decided, after a series of chemical investigations, that Formamint was not a definite chemical compound, but that it was probably a solid solution of formaldehyd in lactose. He proved that when the process of manufacture was carried out in exactly the way called for by the Formamint patents, compounds containing a greater or less per cent. of formaldehyd could be made while the other properties remained similar to those of Formamint. The composition of the final product depended on the proportion of the components used in the process. Therefore Formamint did not form a safe means of uniform dosage.

[25] Thoms: Arb. a. d. Pharm. Inst. d. Universität, Berlin =11=:210, 1914.

As a result of Thoms’ work the German courts held that Formamint was not a new chemical compound. Consequently the Formamint patent (Number 189036) was annulled in Berlin, Nov. 29, 1913.

Again the contention that formaldehyd in the nascent or active condition is less poisonous and irritating than in its ordinary form is contrary to what would be expected from the behavior of such compounds. If it were liberated, as claimed, in the “nascent” condition, it would be, for that very reason, not only more active but also more harmful.

As a matter of fact, Formamint did have an irritant effect on the worker who carried out these investigations. When one tablet was taken each hour for twelve consecutive hours, marked irritation of the intestinal tract resulted. There was almost sufficient nausea to cause vomiting and uneasiness in the alimentary canal following the experiment. When the twenty-four tablets were taken the results were similar but more pronounced. This is decidedly in contradiction to the assertions of the manufacturers.

Otto Seifert,[26] moreover, cites the following:

“By Effects: Only a few patients complain of an unpleasant sharp
taste, burning of the tongue (Seifert, Sklarek). Among the general
symptoms observed are urticaria-like exanthems (Glaser, Roters),
which are accompanied by nausea, vomiting, headache, insomnia
and vertigo, burning and irritability especially in the larynx
(Meissner); phenomena of poisoning (Geissler); gastric disturbances
(Engelmann); renal irritation (Steinhard); unsuited for diabetics
(Voit).”

[26] Seifert, Otto: Die Nebenwirkungen der modernen Arzneimittel, 1915.

The contention that Formamint, when mixed directly with mediums and left in contact with bacteria, will kill the organisms was corroborated. Thus the statements and pictures in the booklet, “The Gospel of Prevention,” which is enclosed with each bottle of Formamint, showing the inhibition of growth of air bacteria on plates containing Formamint are no doubt true and authentic.

Finally, the claim that Formamint is an almost perfect throat disinfectant was by no means confirmed, as a glance at the tables will show. One hour after it is taken, even when a tablet was used each half hour for twelve hours, the number of bacteria in the throat was practically the same as when Formamint was not used. Even ten minutes after taking a tablet the number of bacteria in the throat was never greatly reduced, as is maintained by the manufacturers.

HAS NO SELECTIVE ACTION

Formamint exerts no selective action in killing off the very delicate organisms which are more apt to be pathogenic. When the comparative counts were made on blood agar which would favor the growth of the delicate parasitic organisms, no reduction whatever was shown by the use of Formamint.

The number of streptococci was found to be the same, within limits of experimental error, ten minutes after taking a tablet as it was before the tablet was taken.

Therefore it seems that Formamint fails, as any such germicide would be expected to fail, to kill bacteria in the crypts and recesses of the throat, for when dissolved in the mouth it cannot reach and remain in contact with the organisms long enough to kill them before it is swallowed.

SUMMARY

Summed up, the investigation shows:

1. That the claims made for Formamint are extravagant and misleading.

2. That the recommendations for the use of these tablets may be, in some cases, fraught with danger and are a menace, not only to the health of the individual, but also to the safety of the community.

3. That the claim that Formamint is a definite chemical compound is false.

4. That the use of Formamint may produce marked irritation of the intestinal tract.

5. That Formamint is not a throat disinfectant, as the manufacturers maintain, but its action on the bacteria of the throat is an almost negligible one and dependence on Formamint for the prevention of infection and for curing disease is not only unwise but dangerous.

6. That Formamint conflicts with the rules of the Council. False statements are made with regard to its composition (Rule 1); grossly unwarranted claims are made for its therapeutic properties (Rule 6), and therefore its exploitation to the public (Rules 3 and 4) is a public danger.

It is recommended that this report be published, to call attention not only to the falsity of the claims made for, and the danger in the use of, Formamint, but also to emphasize the utter inefficiency of all such methods of “disinfecting” the throat.--(_From The Journal A. M. A., Aug. 28, 1915._)

HYDRAGOGIN

Report of the Council on Pharmacy and Chemistry

Hydragogin (C. Bischoff & Co., New York, selling agents) is advertised as “a most powerful diuretic and cardiac tonic.” The composition given is:

“Fifteen parts of the remedy contain 0.5 parts oxysaponin, 1.5
parts tincture of digitalis, 2.5 parts tincture of strophanthus,
scillipicrin and scillitoxin, the active principles of scilla
maritima, and alcohol.”

It is not clear from this statement whether 15 parts of Hydragogin contain 2.5 parts of tincture of strophanthus, plus unspecified amounts of scillipicrin and scillitoxin, or 2.5 parts of a mixture, in unspecified proportions, of tincture of strophanthus, scillipicrin and scillitoxin. The activity of strophanthus, after it enters the blood stream, is about fifty times that of digitalis; hence, if the former proportion is the true one, in giving an amount of Hydragogin which ensures the full therapeutic effect of the digitalis, one would administer an almost certainly fatal amount of strophanthus. Whatever the proportion of strophanthus may be, however, the administration of a mixture of digitalis and strophanthus in fixed proportions is indefensible. At times it is advisable to follow one of these drugs with the other in the treatment of cardiac disease. The simultaneous administration of the two continuously in fixed proportions, however, is injudicious, because of the great difference between their rates of absorption and in their activity after they enter the blood stream. The action of digitalis, moreover, persists much longer than does that of strophanthus.

An advertising circular contains the following claim:

“The well-known diuretic properties of digitalis, strophanthus and
squills are greatly enhanced by the addition of the oxysaponin.”

This is not true. Saponins are not synergistic with digitalis therapeutically; on the contrary, they exert a purely deleterious action on the heart when they enter the circulation.

The symptoms of cardiac disease are often difficult to distinguish from the toxic actions of the digitalis bodies. Since these bodies must often be given to the point of beginning toxic action in order to induce the full therapeutic effects, it is obvious that the administration of a mixture of digitalis, strophanthus, saponin and active principles of squill is especially liable to induce serious toxic effects which cannot be distinguished from the symptoms of the disease.

Hydragogin is a shotgun mixture of semisecret composition; it is marketed under a therapeutically suggestive name, and advertised by means of unwarranted therapeutic claims. It is therefore in conflict with Rules 1, 6, 8 and 10. The Council held Hydragogin ineligible for New and Nonofficial Remedies.--(_From The Journal A. M. A., Sept. 4, 1915._)

FILUDINE

Report of the Council on Pharmacy and Chemistry

Filudine is said to be prepared by J. L. Chatelain, Paris, and is sold in this country by Geo. J. Wallau, Inc., New York. It is offered as a remedy for “biliary insufficiency,” “hepatic insufficiency,” “intestinal dyspepsia,” “all affections of the liver (diabetes, cirrhosis, cancer, etc.),” “malaria,” “obesity” and “tuberculosis.”

No quantitative information is furnished as to the composition of the preparation and there are noteworthy discrepancies in the various statements regarding the ingredients. In one number of “Treatment,” a self-styled “Review” of medical literature (actually devoted to advertising the preparations sold by Wallau), we are told that

“This product [Filudine] is a more concentrated and potent extract
of the liver, with which is combined an extract of the spleen. The
liver and the spleen are so intimately interdependent, that the
addition of a splenary extract to the liver extract is a signal
improvement from which a synergistic action results. Thiarféine is
also added, as it helps somewhat to combat the anaemia from which
all diabetics suffer more or less.”

Thiarféine is said to be

“Thiomethylarsinate of Caffein, a new salt discovered by M.
Chatelain.”

Another circular, which gives an imposing formula for “thiarféine” or “thiomethylarsinate of caffein,” states that

“Sulphurated methylarsinate is an arsenical preparation devoid of
all toxicity on account of the intimate joining of its composing
parts.”

And that

“Filudine can never be contraindicated.”

A statement of composition in a later number of “Treatment,” however, says that biliary extracts are components, in addition to the liver and spleen extracts. Moreover, thiarféine, the “new salt discovered by M. Chatelain,” is no longer “thiomethylarsinate,” but “thiocinnamate of caffein”; and a new formula is furnished for it.

We are told that

“Methyl-arsinate cannot be used in cases where fever is present....”

“M. Chatelain at first studied the action of thiomethylarsinate;
clinical and physiological experimentation led him, however, to
adopt thiocinnamate of caffein, of greater activity and with no
contraindications.”

Nevertheless the same absence of contraindications was urged in favor of Filudine when it was said to contain the now discarded thiomethylarsinate of caffein.

The following are some of the unwarranted and even absurd claims:

“Filudine restores the liver’s functions. It is to the liver what
digitalis is to the heart; it overcomes the insufficiency and
stimulates the debilitated organ.”

In malaria “it is the only true specific when associated with
quinine.”

“Filudine is ... the ideal medication for tuberculosis, conforming
as it does with the most recent researches in the therapeusis of
this affection.”

“We will not go as far as to say that Opotherapy _completely
restores_ unhealthy livers, for although the lesions of the hepatic
parenchyma may be obliterated by regeneration, the lesions of
the connective tissues are permanent, and may be observed at the
postmortem examination. The new cells, however, do not present the
same unhealthy conditions as those of the former diseased gland
which they have replaced, and the liver can therefore function
normally, so that the patient lives on; and he is satisfied with
that.”

“Therefore, while regenerating the liver with Filudine, we cleanse
it and combat its congested state with Urodonal. We cause it to
produce urea from the excess of uric acid which it contains.”

“By the judicious and harmonious combination of the beneficial
effects of Filudine and Urodonal, physicians not only possess the
means of treating by rational methods Cirrhosis of the Liver in its
various forms (which is one of the most terrible diseases which can
afflict anyone) but what is still better, _they can cure it_.”

“The liver of a person suffering from obesity being incapable
of fulfilling its functions in regard to the fatty tissues, the
rational and up-to-date method of treatment is therefore to restore
to the system, in the form of Filudine, the liver extracts which
are lacking.”

Filudine is a mixture of semisecret composition. The therapeutic claims are manifestly unwarranted. The name is not indicative of the composition, whatever that may be, and no rational excuse is offered for the combination of liver and spleen extracts (with or without bile extracts) with “thiomethylarsinate” or “thiocinnamate” of caffein.

The Council therefore held Filudine ineligible for New and Nonofficial Remedies.--(_From The Journal A. M. A., Sept. 18, 1915._)

LACTOPEPTINE AND ELIXIR LACTOPEPTINE

Report of the Council on Pharmacy and Chemistry

Mixtures of pepsin and pancreatin are therapeutically irrational; the two substances are not indicated in the same conditions, nor can they act together. Under physiologic conditions, such mixtures are chemically impossible: in a liquid medium the ingredients destroy each other.

Lactopeptin is manufactured by the New York Pharmacal Association, Yonkers, N. Y. It is sold under the claim that it contains, pepsin, diastase, pancreatin, lactic acid and hydrochloric acid. This product was among the first proprietary preparations examined by the Council on Pharmacy and Chemistry. The report of the investigation was published in The Journal, March 16, 1907, p. 959. The preparation was found to be practically inert--“essentially a weak saccharated pepsin,” devoid of tryptic activity.

Six years later it was still widely advertised with the same irrational claims. A referee (A) therefore examined Lactopeptine (powdered) for the Council in 1913, and confirmed the previous findings. The referee’s report was published in The Journal, Aug. 2, 1913, p. 358.

Nearly four months after this publication, the manufacturer protested against the report, maintaining, contrary to the findings of the Council, that Lactopeptine possesses pancreatic activity and contains “loosely combined” hydrochloric acid. Referee A therefore repeated his examination, and a second referee (B), independently, examined specimens of Lactopeptine (powder) purchased on the open market for the purpose shortly before.

A few specimens examined by these two referees showed a slight tryptic activity; most of them showed none. The amount of hydrochloric acid present was insignificant.

The reports of the two referees were referred to the manufacturers, who again protested vehemently against these findings, this time on the ground that the specimens were old. The manufacturers also cited the work of three chemists to disprove the findings of the referees, and demanded that the Council reexamine Lactopeptine, making use of fresh specimens. The Council refused for the following reasons:

1. So long as the packages of Lactopeptine are not dated, the activity of specimens known to be fresh is of no practical importance. The activity of the actual market supply is the only question of interest to the profession. The only fair test is that made on specimens representative of the product sold to the ultimate consumer.

2. The evidence presented by the manufacturers did not warrant a reexamination, since the work of two of the chemists cited substantially corroborates the results obtained by the Council’s referees from the fresher specimens. The figures for tryptic activity obtained by the third chemist cited by the manufacturers could not be accepted by the Council, since it was at variance with all other known results of investigations of Lactopeptine.

3. As stated at the outset, whatever the tryptic activity of the mixture, it is therapeutically useless. A demonstration of tryptic activity in a mixture containing both pepsin and pancreatin is of merely theoretical interest.

Such activity, of course, cannot be expected, even on theoretical grounds, in liquid mixtures like Elixir Lactopeptine.

The Council therefore again declared Lactopeptine (powder and tablets) and Elixir Lactopeptine ineligible for New and Nonofficial Remedies and authorized publication of the following statement.

W. A. Puckner, Secretary

_THE COUNCIL’S REPORT_

Lactopeptine powder (New York Pharmacal Association, Yonkers, N. Y.) was examined by the Council in 1907. At that time it was claimed to contain

“... the five active agents of digestion--pepsin, diastase (veg.
ptyalin), pancreatin, lactic acid and hydrochloric acid--combined
in the proper proportion to insure the best results.”

The examination showed that the preparation was essentially “a weak saccharated pepsin,” containing but small amounts of pepsin, no hydrochloric acid, or mere traces only, and no diastase or pancreatin (The Journal, March 16, 1907).

In 1913, the product was reexamined, because the claims, as to both composition and therapeutic value, were still being made. Samples were tested both of the American product, and of a British product from John Morgan Richards & Sons, London. The original findings were confirmed and the results were published in The Journal, Aug. 2, 1913, p. 358. Nearly four months later (November 24) the New York Pharmacal Association wrote to the Council, objecting to the findings and maintaining that Lactopeptine possesses pancreatic activity and contains (“in loose chemical combination”) hydrochloric acid. In accordance with the custom of the Council, the work was sent back for review to the referee (A), whose conclusions were then tested by a second referee (B), a physiologic chemist, not a member of the Council, selected because of his special knowledge of the subject.

In December, 1913, Referee A made a large number of new tests to determine proteolytic and amylolytic power. His results show that the ferment activity of the preparation is so low as to merit no recognition in practical use. The tests also show that the amount of lactic acid or “loosely combined HCl” (or both) present is too small to have any appreciable physiologic activity and therefore to be of any therapeutic value.

Nine samples of Lactopeptine purchased in the open market in December, 1913, and January, 1914, were examined by Referee B early in 1914. His studies show absence of amylase in all samples; presence of pepsin, giving weak reactions even when compared with those of old pepsin preparations; complete absence of trypsin in seven out of nine samples, tryptic reaction being obtained in two samples, in one of which the reaction, “slight at best and of no practical import,” was obtained only after treatment for twelve hours or more.

The presence of tryptic activity in two out of the nine samples may be due to the fresher condition of these specimens, as indicated by the serial numbers. The evidence shows that it is a commercial impossibility to market mixtures of pepsin, pancreatin and lactic acid so that they can display any material tryptic activity.

It should be reaffirmed that mixtures combining peptic and pancreatic activities are not feasible, because pepsin cannot act except in the presence of acid, and pancreatin is destroyed by acid and by peptic activity. Furthermore, in conditions in which pancreatin is called for, pepsin is not, and vice versa; therefore the administration of mixtures of pepsin and pancreatin would be unjustified, even if both constituents could be expected to exert activity.

The foregoing observations apply to Lactopeptine in powder and tablet form.

While mixtures of pepsin and pancreatin are unscientific and unjustified, theoretically the two substances may coexist in a solid preparation, and the activity of such a preparation is consequently a proper subject of investigation. Theoretically as well as practically, however, pepsin and pancreatin cannot exist together in solution. The claims made for Elixir Lactopeptine and all other liquid preparations sold as mixtures of pepsin and pancreatin are therefore impossible. The Council has previously taken action (The Journal, Feb. 2, 1907, p. 434) refusing to approve for inclusion with New and Nonofficial Remedies such preparations, calling the attention of the medical profession and of manufacturers to their worthlessness, and requesting the American Pharmaceutical Association to instruct its committee on the National Formulary to omit from the next edition of that work a liquid preparation of pepsin and pancreatin recognized under the title of “elixir digestivum compositum.”

It is recommended that the Council reaffirm this previous action, and that Lactopeptine and Elixir Lactopeptine be declared ineligible for New and Nonofficial Remedies because of conflict with Rule 10 (“No article will be admitted which, because of its unscientific composition, is useless or inimical to the best interests of the public or of the medical profession”).

Manufacturers’ Protest and Council’s Answer

The foregoing was submitted, together with the findings of the two referees, to the manufacturers. They protested again, alleging that:

AGE OF SPECIMENS

_First._--The specimens of Lactopeptine examined by the second referee were old. The dates of manufacture corresponding to the several batch numbers are supplied by the manufacturers as follows:

2275 (Powder) September, 1908
2301 (Powder) June, 1909
2312 (Powder) December, 1909
2348 (Powder) October, 1911
2352 (Powder) December, 1911
2364 (Powder) July, 1912
2374 (Powder) March, 1913
2383 (Powder) October, 1913
1638 (Tablets) October, 1911

The manufacturers assert that they do not understand how specimens of these ages could have been purchased on the open market in 1913 and 1914, inasmuch as their agents are and long have been instructed to take up from the druggist all lots of Lactopeptine which, as indicated by the batch numbers, have attained “any appreciable age.” The age of the specimens, the manufacturers declare, deprives the table in the second referee’s report of “all significance or interest.”

As previously stated, however, the specimens of Lactopeptine examined were purchased on the open market in various localities in unbroken packages, in December, 1913, and January, 1914. They thus represent stock used in filling physicians’ prescriptions or sold to the public. Neither the referees nor any one connected with the Council had any means of knowing the age of the specimens until the dates of manufacture were furnished by the New York Pharmacal Association. The first tests of the second referee were made in February, 1914, on Specimens 2374 and 2383, which were then, it would appear, about one year old and four months old, respectively. The Council has repeatedly urged that pharmaceutical substances which are subject to deterioration should be dated by the manufacturer, and a similar suggestion has been made by the Bureau of Chemistry of the U. S. Department of Agriculture concerning mixtures containing enzymes. Notwithstanding the instructions which the New York Pharmacal Association claims to have given its agents, the market supply of Lactopeptine in December, 1913, and January, 1914, was not composed of new stock, and until the manufacturers adopt the practice of dating packages, there can be no assurance that it will be fresh. In this connection, it is of interest to note that the Bureau of Chemistry of the U. S. Department of Agriculture has issued a warning that it will judge such products by the degree of their activity when they reach the consumer, i. e., as they are found on the market.

REPORTS OF OTHER CHEMISTS

_Second._--The New York Pharmacal Association cites the work of several chemists, who have examined Lactopeptine and report the presence of tryptic activity. Dr. S. R. Benedict in December, 1913, reported to the Council “distinct” tryptic activity (digestion in twelve hours by Lactopeptine of 4.2 times its weight of fibrin containing 50 per cent. moisture) in specimens examined by him. These specimens were numbered 2382, and were therefore probably manufactured in October, 1913; compare the dates furnished by the manufacturer for the specimens used by the second referee. No tests against other preparations possessing tryptic activity are reported, and Dr. Benedict expressly disclaims any opinion as to the therapeutic value of the preparation.[27] Dr. P. B. Hawk, whose report was submitted by the manufacturers, found in Lactopeptine by Fermi’s method one-fifth tryptic activity of that of Merck’s pancreatin, and by Grützner’s method an activity of 18 per cent. of the pancreatin. A test for the production of tryptophan was reported positive. The New York Pharmacal Association also submitted a report from Dr. A. W. Balch, who found pepsin, rennin, trypsin, steapsin, amylopsin and lactic acid present in Lactopeptine; also an amount of combined hydrochloric acid in 1 gm. the equivalent of 1.05 c.c. tenth normal solution or 0.00383 gm. hydrochloric acid. (He reports digestion in twenty-four hours by Lactopeptine of 25 times its own weight of fibrin. “An active extract of pancreas reacted exactly like the Lactopeptine solution.”) The serial numbers of the specimens tested by Hawk and Balch are not given, but no doubt they were fresh.

[27] Dr. Benedict’s personal communication to a member of the Council is as follows:

“In the report of the Council upon Lactopeptine which you sent to me, I find the following statement: ‘Careful examination failed to show the presence of either diastase or pancreatin.’ In this connection I will cite to you the following experiment carried out by myself: A package containing a 1-ounce bottle of Lactopeptine (powder) with seal unbroken was purchased in the open market and opened in this laboratory. The label bore the special Number 6 2382. Two hundred milligrams of this product was dissolved in 50 c.c. of a 0.25 per cent. solution of sodium carbonate in water. This solution was divided into two portions of 25 c.c. each. One of these portions was boiled at once, and after cooling was added to 1 gm. of moist fibrin contained in a flask. The other portion (unboiled) was also added to 1 gm. of moist fibrin contained in a flask. Both flasks (after addition of 5 c.c. of toluene to each) were stoppered and placed in an incubator at 37 degrees, and left there for twelve hours. Examination of the two flasks at the end of this period showed that the one to which the unboiled solution of Lactopeptine [powder] had been added contained much less solid protein than did the other. Although this fact was obvious to the naked eye, the exact extent of digestion in the two flasks was determined by heating both to boiling, acidifying with acetic acid, diluting to definite volume, filtering and determining the nitrogen in the filtrate by Kjeldahl’s method. Subtracting the trace of nitrogen contained in the filtrate of the control flask, the results showed that 42 per cent. of the original fibrin present had been dissolved by the unboiled Lactopeptine solution. This can be ascribed only to tryptic activity under the conditions of this experiment. Furthermore, this is not simply a ‘trace’ of activity, but is at least sufficiently marked to warrant a statement that this sample showed a distinct tryptic activity. Inasmuch as I have obtained exactly similar results with two other samples of Lactopeptine (powder) (these being the only ones I have examined), I am inclined to question the correctness of the Council’s statement regarding the absence of trypsin from this preparation. [As noted above, a fresh preparation was used.--Ed.]

“May I again add that I am making no statement regarding therapeutic value of preparation, and that I have no opinion upon that matter one way or the other? My work was undertaken solely out of interest to see whether trypsin could exist in the powder (which gives a markedly acid solution when dissolved in water). The Elixir Lactopeptine could theoretically show no tryptic activity, nor have I found any trace of such activity in one sample of the Elixir examined.

“In making use of any of the contents of my letters kindly include the statement that my work upon Lactopeptine was done without remuneration of any kind, and was done only for the scientific interest attached to the question.”

CONCLUSIONS

The New York Pharmacal Association demanded that the referee reexamine Lactopeptine, making use of fresh specimens. The Council held that this was unnecessary, for the following reasons:

1. The previous finding of the Council, that specimens of Lactopeptine found on the open market are essentially weak saccharated pepsins, is not to be refuted by examination of fresh specimens. Even if it be assumed that all old specimens of Lactopeptine have been withdrawn from the market since the last purchase of specimens for the use of the Council’s referee, there can be no assurance that the stock will be constantly kept fresh. Unless the manufacturers date their product, physicians cannot know that their prescriptions are filled with fresh material. Nor is it reasonable to ask that the Council examine the market supply of any given proprietary at a time selected by the manufacturers.

2. Without entering into all questions of detail in the analyses, the Council is willing to accept the reports of Drs. Benedict and Hawk as representative of fresh Lactopeptine powder. It is therefore unnecessary for the Council to make further experiments along this line. The results of these two chemists in no wise contradict the conclusions of the Council’s referees, being comparable with those obtained by the referee on the fresher specimens used by them. The experiments of Drs. Hawk and Benedict show a degree of tryptic activity which, though chemically not negligible, is quite without significance practically, even if it could be assumed that the trypsin in the fresh Lactopeptine escaped destruction in the stomach. The figures for tryptic activity given by Dr. Benedict do not differ materially from those of the first referee. Those of Professor Hawk show a tryptic activity of from 18 to 20 per cent. of that of commercial pancreatin--and commercial pancreatins ordinarily are of low tryptic activity, if not inert (see Long and Muhleman: _Arch. Int. Med._, February, 1914, p. 314.) The reports of these chemists present no reason for changing the conclusion that “it is a commercial impossibility to market mixtures of pepsin, pancreatin and lactic acid so that they can display any material tryptic activity.”

The results which Dr. Balch obtained in a test for tryptic activity show a marked discrepancy with those obtained by Drs. Hawk and Benedict, not to mention the Council’s referees, and also with the fact that only about 11 per cent. of “pancreatin” is claimed in the published formula of Lactopeptine. The Council is unable to accept Dr. Balch’s result for trypsin or rennin as reliable. His other results are without significance and call for no special comment.

3. Even if tryptic activity were conceded to Lactopeptine, the preparation, like all preparations containing pepsin and pancreatin, would still be, as previously stated, therapeutically irrational.

The Council approved the report.

Report of Referee A

In view of the manufacturer’s reiteration of the claims for Lactopeptine powder, I have carried out further experiments to determine its proteolytic and amylolytic power.

For the proteolytic test I used fresh, well washed fibrin and examined samples of Lactopeptine powder numbered as follows:

No. 1. A part of the English product examined and reported on last spring.

No. 2.--A fresh bottle obtained at a Chicago retail drug store in December, 1913.

No. 3. A fresh bottle obtained at a Chicago retail store in December, 1913.

Portions of 1 gm. each of these samples were mixed with 5 gm. fibrin, 100 mg. of sodium carbonate and 50 c.c. of water in flasks. A little toluene was added to each flask, which was then closed with a tuft of cotton and the mixtures were incubated at 40 degrees through twenty-four hours. At the end of that time there was no marked change in the quantity of the fibrin remaining in each flask, the larger part by far being undigested.

As a control I used the sample of an active commercial trypsin, of which I added 500 mg. to the same quantity of water, fibrin and sodium carbonate. This was digested in the same bath at the same time. The digestion was practically completed in less than ten minutes, only minute flakes of the fibrin remaining.

It is evident that the digestive power of the Lactopeptine must be extremely low, and only a small fraction of that exhibited by a commercially good trypsin.

In an experiment with the English sample carried out through nineteen hours as above, using 2 gm. of fibrin and 100 mg. of ferment, it was found by nitrogen tests on the filtrate that about 12.2 per cent. of the protein had been brought into solution, an amount which is practically without importance in a digestion of such duration.

To test the starch digestive power I have made a large number of experiments. In a series just completed I mixed 1 gm. portions of Samples 1 and 2 with water to make 100 c.c. volumes. Before making up to the final volumes 0.5 c.c. of normal sodium hydroxid was added to neutralize the slight acidity of the ferment as shown by phenolphthalein.

Of these mixtures 4, 6, 8 and 10 c.c. portions were mixed with 50 c.c. of 1 per cent. starch paste and incubated at 40 degrees to find the colorless end-point in the starch digestion, by the iodin test.

At the end of twenty-two hours the iodin reaction was as strong as at the beginning, indicating no appreciable starch digestion.

To the flasks in which no digestion had taken place under these conditions, 5 mg. of a pancreas ferment was added. This gave an almost immediate conversion to the colorless end-point. This ferment was a sample of Holadin which had been in the laboratory about a year. The 5 mg. completed the reaction to the colorless end-point in less than ten minutes.

In a similar test I used 2 gm. of Lactopeptine No. 3, made up to 100 c.c. with 1.2 c.c. of normal alkali. Ten and 15 c.c. portions were incubated with 50 c.c. of 1 per cent. starch paste through twenty hours at 40 degrees with no apparent result. The Holadin then added, 5 mg. being used, completed the conversion in less than ten minutes.

This shows that the medium was a proper one for the test and that the Lactopeptine must be extremely weak. No sugar tests were made because the Lactopeptine contains milk sugar to the extent of about 60 per cent.

Similar results for both protein and starch digestives have been obtained in a large number of experiments. These here quoted show that the ferment activity of the preparation is so low as to merit no recognition practically. The digestion of a few milligrams of fibrin or starch after many hours of contact, while being perhaps scientifically possible, is of no value when we come to a consideration of the use of such bodies as digestive ferments in medicine.

The amount of lactic acid or “loosely combined HCl” present in Lactopeptine is very small, since the total acid which may be titrated by sodium hydroxid and phenolphthalein is measured by 0.5 c.c. of the normal hydroxid for 1 gm. of the Lactopeptine powder, in the mean. In different samples examined the range was found to be from 0.41 c.c. to 0.6 c.c. Tests with methyl orange, methyl red and other indicators showed that the free acidity is but trifling; if the whole of this acid, as measured by phenolphthalein, were calculated to HCl, the amount would be too small to have any appreciable physiologic activity, in view of the daily dose recommended, 10 to 20 grains of the powder.

Report of Referee B

The following table gives a summary of the results of my investigations on Lactopeptine. The numbers in the extreme left-hand column are the manufacturer’s identifying marks. These, it is assumed, run serially, the higher numbers indicating fresher specimens.

TABLE SHOWING ENZYMIC POWER OF LACTOPEPTINE PREPARATIONS

Amylase Pepsin Rennin Trypsin Lipase
2275 - + + - -
2301 - + + - -
2312 - + + - -
2348 - + + - -
2352 - + + - -
2364 - + + +(?) -
2374 - + + - +(?)
2383 - + + + +(?)
1638 (tablets) - + + - -
Pancreatin (Old) - .. .. ++ -

The conclusions in the foregoing summary depend on the following criteria:

_Amylase_: removal of starch (paste), _small in proportion to begin with_.

_Pepsin_: solution of small shreds of _fresh_ fibrin in acid media.

_Rennin_: curdling of milk in moderate excess.

_Trypsin_: solution of small shreds of _fresh_ fibrin in neutral and alkaline media, and tryptophan test.

_Lipase_: coloration of litmus-milk; exact _color_ controls.

All tests were suitably controlled. The responses for pepsin were weak even when compared with those of old pepsin preparations.

In the table above, the interrogation points in parentheses (?) refer to results that were obtained after treatment for from twelve to twenty-four hours and indicates that the change was slight at best and of no practical import.--(_From The Journal A. M. A., Oct. 23, 1915, with additions._)

IODUM-MILLER AND IOD-IZD-OIL (MILLER’S)

Report of the Council on Pharmacy and Chemistry

The Council adopted the following report and authorized its publication.

W. A. Puckner, Secretary.

A referee has submitted to the Council the following report of the Chemical Laboratory of the American Medical Association on Iodum-Miller and Iod-Izd-Oil (Miller’s) (Iodum-Miller Co., Kansas City, Mo.):

The unsatisfactory statements made in regard to the composition of Iodum-Miller and the far-reaching therapeutic recommendations for it induced the laboratory to make a chemical examination of the preparation. It claimed more or less directly that the preparation is entirely new and possesses novel characteristics.

It is asserted that

“Iodum-Miller is made from Soot Iodine, which is our own product.
This Soot Iodine is SOLUBLE IN WATER before being combined with its
base C.P. Glycerine.”

No information regarding “soot iodine” is offered and an inquiry sent to the proprietors by a physician brought only the noncommittal reply that “soot iodine”

“is made from Resublime [resublimed?] Iodine by a chemical process
which renders it soluble in water before being combined with its
base.”

Iodum-Miller is said to contain

“Active Free Iodine 2.2 grams per 100 c.c., 10. grains per fluid
ounce, 1.7% by weight.”

“In addition to the active free iodine ... IODUM-MILLER carries a
still greater per cent of Iodine in its basic combination....”

According to the label, the preparation is

“An Iodine for External and Internal use ... 45 drops equals 1 dr.
by weight. Each drop equals the per cent. of iodine in 1 gr. potas.
iodide.”

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The Propaganda for Reform in Proprietary Medicines, Vol. 2 of 2Chapter X: Introduction: The Council on Pharmacy and Chemistry was established (3)

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