Chapter XXVII: Appendix (8)

The Council continues to hold that intravenous medication, generally, is not as safe as oral medication even with relatively harmless substances (a fact again illustrated by the results of Hanzlik and Karsner, 1920, _Journal Pharmacology and Experimental Therapeutics_, 14, 379), and that it does not give “improved clinical results” except under rather narrowly confined circumstances--namely, if the drug undergoes decomposition in the alimentary tract, if it is not absorbed, if it causes serious direct local reaction or if time is an urgent element. Each intravenous preparation for which advantage over oral administration is claimed, directly or by implication, must be examined from these points of view.

The Council has recognized intravenous preparations which satisfied these requirements. It is evident, however, that hexamethylenamin, sodium iodid and sodium salicylate do not. When given orally they do not undergo material decomposition in the digestive tract, they are rapidly absorbed, they cause no direct local reaction, and in the conditions in which they are used the hour or so which is required for absorption is immaterial, especially as they are used continuously for some time. Mercuric chlorid does indeed produce some local irritation, but there is as yet no convincing evidence that its intravenous injection causes less injury than oral administration. More experience under controlled conditions is needed before the intravenous use of mercuric chlorid can be approved. Especially objectionable are the fixed proportion mixtures of sodium iodid with sodium salicylate and with hexamethylenamin. The dosage of all three drugs has to be adapted to individual conditions. This is impossible when giving them in fixed proportions.

The Council voted not to accept “Loeser’s Intravenous Solution of Hexamethylenamin,” “Loeser’s Intravenous Solution of Hexamethylenamin and Sodium Iodid,” “Loeser’s Intravenous Solution of Sodium Salicylate,” “Loeser’s Intravenous Solution of Salicylate and Iodid,” “Loeser’s Intravenous Solution Sodium Iodid” and “Loeser’s Intravenous Solution of Mercury Bichlorid” for New and Nonofficial Remedies because they are sold under misleading claims regarding their alleged safety and efficiency. In view of this fundamental objection the individual claims for each preparation were not passed on.--(_From The Journal A. M. A., April 16, 1921._)

“NATIONAL IODINE SOLUTION” NOT ADMITTED TO N. N. R.

Report of the Council on Pharmacy and Chemistry

The Council has authorized publication of the following report.

W. A. Puckner, Secretary.

“National Iodine Solution” is a proprietary sold by the National Drug Co., Philadelphia, Pa. From inquiries received by the Council on Pharmacy and Chemistry it is evident that the product is extensively brought to the attention of physicians by means of circulars. The name implies that it is a solution of iodin and the inference is given that it has the advantages of iodin without the disadvantages.

COMPOSITION

In view of the foregoing, the Council took up the investigation of “National Iodine Solution,” and in turn asked the A. M. A. Chemical Laboratory to analyze it. The chemist’s report follows:

According to the label of National Iodine Solution, “each fluidounce represents three grains Proteo-albuminoid compound of iodin (National)”; also an alcohol declaration of 7 per cent. is made. Otherwise no information is given as to the composition either of the “solution” or of “Proteo-albuminoid compound of Iodine.”

Each bottle contained about 115 c.c. (nearly 4 ounces) of a yellowish solution, acid in reaction, having an odor resembling witch hazel; its specific gravity at 25 C. was 0.9860. Qualitative tests indicated the presence of zinc, alcohol, sulphate, an iodin compound (the solution gave tests which indicated a very small amount of free iodin; most of the iodin was in the form of ordinary iodid), a small amount of vegetable extractives, and traces of aluminum and potassium. If any protein was present, it was in amounts too small to be identified, though a small amount of a nitrogenous compound was present. The amount of solids in “National Iodine Solution” was equivalent to 0.72 per cent, and the amount of ash, to 0.2 per cent. Quantitative estimations yielded the following:

Alcohol (by volume) 7.0 per cent.
Zinc (Zn++) 0.096 per cent.
Iodin (free and combined) 0.029 per cent.
Sulphate (SO₄--)   0.146 per cent.
Protein (N × 6.36) 0.012 per cent.

The above findings indicate that each 100 c.c. contains about 7 c.c. of alcohol, 0.5 gram of zinc sulphate U. S. P. (ZnSO₄+7H₂O.), 0.03 gram of iodin, 0.01 gram of protein (calculated as such from nitrogen times the factor 6.36) and some hamamelis water. Expressed in equivalent apothecary terms, each fluidounce contains essentially:

Zinc sulphate 2-1/3 grains
Iodin (free and combined) 1/8 grain
Protein 1/25 grain
Alcohol 34 minims

This amount of alcohol is equivalent to about 3-1/2 fluidrams of witch hazel water. Although the label states that each fluidounce contains three grains of “proteo-albuminoid compound of iodine,” yet the sum of the protein (calculated from nitrogen content) and iodin components is equivalent to less than 1/5 grain.

“National Iodine Solution” appears to be very similar to “Gonocol” (The National Drug Co., Philadelphia, Pa.), which was analyzed by the Bureau of Chemistry of the U. S. Department of Agriculture. The bureau stated that “it [Gonocol] consisted essentially of an aqueous solution of zinc sulphate, hamamelis water, a small amount of alcohol, 0.38 grain of iodin, and 0.36 grain of protein per fluidounce.”

It is evident that “National Iodine Solution” is not a solution of free elementary iodin as the name suggests; instead it appears to be a solution of zinc sulphate in witch hazel water containing less than 0.03 per cent. of combined iodin and _not more than a trace of free iodin_. “National Iodine Solution” is one more to be added to that already long list of proprietaries which makes capital of the high esteem in which physicians hold iodin.

THE CLAIMS

An advertising circular sent to physicians begins:

“_Dear Doctor_: We beg to suggest a line of treatment while using
National Iodine Solution which our many years of experience has
proven to us to give the best and quickest results in the treatment
of inflammation of the urethral tract ...”

In it are given directions for the treatment of “acute gonorrhea, male,” “anterior urethritis,” “anterior-posterior urethritis,” “ardor urinæ and chordee,” etc., by means of National Iodine Solution and other proprietaries of the National Drug Company’s make. In fact the solution is claimed to be “Indicated in All Conditions of Urethra Accompanied by a Discharge.”

COMMENT AND CONCLUSIONS

The therapeutic claims made for “National Iodine Solution” are unwarranted. Such a solution is not indicated in all conditions of the urethra accompanied by discharge. The advice contained in the circular is equivalent to mail-order treatment of gonorrhea.

It is of interest to note that the claims for an identical or a similar solution prepared by the National Drug Company as a treatment for gonorrhea and intended for use by the laity, has been adjudged misbranded by the federal authorities (Notice of Judgment No. 8150, issued Jan. 25, 1921) in that it misled and deceived the purchaser or purchasers thereof in the statements regarding the therapeutic or curative effects of the article, which falsely and fraudulently represent it to be indicated in all conditions of the urethra accompanied with a discharge, “whereas in truth and in fact it was not.”

The Council would emphasize that if physicians give heed to advertising such as that sent out by the National Drug Company for this preparation the medical profession cannot with good grace protest against the routine treatment of venereal diseases by quacks and “patent medicine” venders.--(_From The Journal A. M. A., June 4, 1921._)

MON-ARSONE NOT ADMITTED TO N. N. R.

Report of the Council on Pharmacy and Chemistry

The Council has authorized publication of the following report.

W. A. Puckner, Secretary.

Mon-Arsone is offered by the Harmer Laboratories Company as “a new and non-toxic arsenical for the treatment of syphilis.” In the advertisements for Mon-Arsone it has been claimed that with this drug “the toxic, corrosive and uncertain reactions attending the use of arsphenamine have been entirely eliminated” and that “it has a therapeutic value equal to arsphenamine, but extensive case reports fail to record the slightest toxic reaction following its use.”

According to the manufacturers, Mons-Arsone is disodiumethylarsonate, the sodium salt of ethylarsonic acid, derived from arsenic acid by replacement of one hydroxyl group by the ethyl group--AsO(CH₂CH₃)(OH)₂. Mons-Arsone is related to sodium cacodylate, which is the sodium salt of dimethyl-arsenic acid--AsO(CH₃)₂OH--derived from arsenic acid by replacement of two hydroxyl groups by two methyl groups. Ethylarsonic acid and its potassium salt were described by La Coste[139] more than thirty-five years ago, and the use of the sodium salt of methylarsonic acid was proposed in France some years ago. The Harmer Laboratories Company claims originality for Mons-Arsone in that it was the first to prepare the sodium salt of ethylarsonic acid and to propose its therapeutic use.

[139] La Coste: Annalen der Chemie (Liebig’s) 208: 34.

It was reported several years ago by Castelli[140] that sodium cacodylate and the sodium salt of methyl arsenic acid were devoid of effect on experimental trypanosomiasis and spirochete infections. Careful clinical observations in this country by H. J. Nichols[141] and H. N. Cole[142] have demonstrated the inefficacy of sodium cacodylate in the treatment of human syphilis.

[140] Castelli, G.: Arch. f. Schiffs- u. Tropen-Hyg. 16: 605, 1912.

[141] Nichols, H. J.: Salvarsan and Sodium Cacodylate, J. A. M. A. 56: 492 (Feb. 18) 1911.

[142] Cole, H. N.: A Study of Sodium Cacodylate in the Treatment of Syphilis, J. A. M. A. 67: 2012 (Dec. 30) 1916.

Animal experiments carried out in the U. S. Hygienic Laboratory by Voegtlin and Smith[143] show that Mon-Arsone is devoid of any practical trypanocidal action. Thus the “therapeutic ratio” (the ratio of the minimal effective dose to the lethal dose) was about 1, that is, it was effective therapeutically only in approximately fatal doses; the therapeutic ratio for arsphenamine in similar conditions was 17, and that of neoarsphenamine, 28.

[143] Voegtlin, Carl, and Smith, H. W.: J. Pharmacol. and Exper. Therap. 16: 449, 1921.

The findings that sodium dimethylarsenate (sodium cacodylate), sodium methylarsenate, and sodium ethylarsenate are devoid of any practical trypanocidal action and the conclusion that sodium cacodylate is inefficient in the treatment of human syphilis does not prove that Mon-Arsone is without effect on the disease. These findings, however, certainly demand convincing therapeutic evidence to warrant the recommendation for the use of the drug in the treatment of syphilis--particularly because the drug is proposed as a substitute for arsphenamine, the value of which is established.

When the Council first took up the consideration of Mon-Arsone, the only evidence for the claim that it “has a therapeutic value at least equal to that of arsphenamine” consisted, with one exception, of reports from those who had experimented with the drug for the Harmer Laboratories Company, including a report by B. L. Wright, L. A. Kennell, and L. M. Hussey,[144] the latter of the Harmer Laboratories Company. These reports appeared to show that the administration of Mon-Arsone caused less reaction than arsphenamine, and that the immediate effects, judged by clinical symptoms and the response to the Wassermann test, appeared to be good. These trials extended over too short a period of time to permit judgment as to the permanence of the results. A report by an independent observer seemed to indicate that Mon-Arsone does not have the sterilizing action on syphilitic lesions which it is usually believed arsphenamine exercises.

[144] Wright, B. L.; Kennell, L. A., and Hussey, L. M.: M. Rec. 97: 607 (April 10) 1920.

After examining the available evidence, the Council advised the Harmer Laboratories Company that the claim that Mon-Arsone has a therapeutic value equal to arsphenamine appeared unwarranted; that, in the opinion of the Council, Mon-Arsone should not be used except under conditions that justify the experimental trial of an unproved drug, and should not be used in a routine way until the permanence of its effects has been established; and consequently any advertising propaganda for the drug by the Harmer Laboratories Company was to be deprecated.

In its reply the Harmer Laboratories Company admitted that its advertising claim, that Mon-Arsone was at least equal to arsphenamine therapeutically, had been based on reports on fifty cases and on additional reports that were beginning to come in at that time. The Harmer Laboratories Company submitted a list of hospitals and physicians using Mon-Arsone. A letter of inquiry sent by the Council to those who, according to the names in the list supplied by the Harmer Laboratories Company, had used Mon-Arsone, brought seven replies.

The clinical evidence contained in these replies was to the effect that Mon-Arsone had been used in the various types of syphilis and that there was a certain beneficial effect, both clinically and as shown by the Wassermann reaction. In certain instances the Wassermann reaction changed from a four plus to a negative reaction. The reports showed that the efficiency of Mon-Arsone as compared with that of arsphenamine preparations has not been adequately studied. One physician who has used Mon-Arsone extensively reports that in many of the cases treated there seemed to be nearly as good results from the use of Mon-Arsone as is frequently obtained in the use of arsphenamine. He reports, however, that it was necessary in eleven out of one hundred cases to change from Mon-Arsone to neoarsphenamine.

In view of the fact that there is definite lack of evidence to show that Mon-Arsone is the equal of arsphenamine therapeutically, and because of the reports that in some cases it is inferior, Mon-Arsone should not be used in the treatment of syphilis generally until its therapeutic status has been more rigidly investigated and conclusive evidence of its superiority to arsphenamine preparations obtained.

The Council voted not to admit Mon-Arsone to New and Nonofficial Remedies and reaffirmed its conclusion that the claim that Mon-Arsone has a therapeutic value equal to that of arsphenamine is premature and unwarranted; that Mon-Arsone should not be used except under conditions that justify the experimental trial of an unproved drug; and that the advertising propaganda for the drug by the Harmer Laboratories Company is to be deprecated.

* * * * *

When the preceding report was sent to the Harmer Laboratories Company, the firm submitted a reply in which it was stated:

1. That in certain instances patients improved under Mon-Arsone who, previously, had not improved under arsphenamine, and that this should be taken to offset the report of the one hundred cases in which the use of Mon-Arsone had to be abandoned in 11 per cent. of the cases.

2. That the Harmer Laboratories Company has abandoned the claim that Mon-Arsone is therapeutically equal to arsphenamine and that it now furnishes the drug to such men as care to use it simply on the basis of its special and useful characteristics.

The Council heartily endorses the recent warning against the use of untried medicaments which was issued by the U. S. Public Health Service.[145]

[145] J. A. M. A. June 12, 1920, p. 1654.

Since the Council’s report was prepared a report on the effects of Mon-Arsone on experimental syphilis has been published by Nichols,[146] from the Division of Laboratories, Army Medical School, which concludes:

1. Disodium-ethylarsinate, or mon-arsone, tested on rabbits infected with syphilis shows no spirocheticidal power. The tissues are fatally poisoned as soon as or before the spirochetes are affected.

“2. For its practical use in syphilis there is no such germicidal basis as exists in case of the arsphenamine group.”--(_From The Journal A. M. A., June 18, 1921._)

[146] Nichols, H. J.: The Spirocheticidal Value of Disodium Ethyl Arsenate (Mon-Arsone), J. A. M. A. 76: 1335 (May 14) 1921.

OXYL-IODIDE NOT ADMITTED TO N. N. R.

Report of the Council on Pharmacy and Chemistry

“Oxyl-Iodide” (Eli Lilly and Co.) is said to be the hydroiodid of cinchophen and the claim is made that it exerts the effects of cinchophen and of iodid. Because of inquiries which have been received the Council decided to determine the eligibility of “Oxyl-Iodide” for New and Nonofficial Remedies. Dr. P. J. Hanzlik--formerly Associate Professor of Pharmacology at Western Reserve University School of Medicine, now Professor of Pharmacology at Leland Stanford Junior University Medical School--who has made a study of the action of salicylates and cinchophen, was asked to report on the therapeutic value and the rationality of “Oxyl-Iodide.” This he consented to do and his report appears below.

After considering Doctor Hanzlik’s report, the Council declared “Oxyl-Iodide” inadmissible to New and Nonofficial Remedies because it is an irrational combination, marketed under claims that are unproved and consequently unwarranted.

W. A. Puckner, Secretary.

“Oxyl-Iodide,” marketed by Eli Lilly & Co., is claimed to be the hydroiodid of phenylcinchoninic acid, containing 33 per cent. of iodin and 67 per cent. of phenylcinchoninic acid (cinchophen). Its solubility resembles that of cinchophen, being low in water and acid mediums, and higher in the presence of alkalis. Whether “oxyl-iodide” is decomposed into its constituents in the presence of alkalis does not appear to have been determined. However, if this were the case, the intestine, after administration of “oxyl-iodide,” would contain cinchophen and sodium iodid in the same forms as if these agents were administered individually so that nothing would be gained by administering “oxyl-iodide.” Being, like cinchophen, practically insoluble in acid mediums, “oxyl-iodide” would have no advantage over the latter so far as gastric irritation is concerned.

DOSAGE

The dosage advised is from one to three tablets containing 3 grains (0.2 gm.) each of “oxyl-iodide.” The total dosage would depend on the condition to be treated. In rheumatic fever, which requires a full therapeutic or so-called, “toxic” dose of cinchophen, about 12 to 13 gm. would be administered intensively. Since each tablet of “oxyl-iodide” contains 0.13 gm. of cinchophen, the total number of tablets of “oxyl-iodide” required would be 100, or two and one-half bottles of forty tablets each. At the same time the patient would receive 6.6 gm. of iodin (as iodid). This might be distinctly objectionable because of the production of the disagreeable symptoms of iodism in some persons, and indicates that the fixed proportion of the iodin constituent would be objectionable.

Even a smaller dosage, such as 5 gm. of cinchophen, which gives partial relief in rheumatism and similar conditions, would still require a patient to take a full bottle, or forty tablets, of “oxyl-iodide,” and at the same time about 2.7 gm. of iodin would have to be ingested.

Furthermore, rheumatic fever, the arthritides, gout and related conditions in which cinchophen is indicated do not require iodid. Therefore, “oxyl-iodide” would not be the remedy of choice in these conditions, and its use would be irrational and illogical.

ACTIONS

No data on the pharmacologic actions of “oxyl-iodide” are presented in the manufacturer’s literature. Presumably, the compound would exhibit the actions of its individual components, i. e., cinchophen and iodin (as iodid), though probably less efficiently, owing to its low solubility. This is also indicated by the following statements of the manufacturer: “The analgesic action of ‘oxyl-iodide’ is gradual. A word of caution is necessary to those who may expect immediate relief from pain.” Therefore, why use “oxyl-iodide” in place of more dependable analgesics, such as salicylate or cinchophen. The following statements appear far-fetched: “There is a stimulation of the endocrines which is perhaps more marked in the thyroid gland, although it is probably shared by the pituitary and other glands which function in a chain-like control.... There is stimulation of cells with increased flow of secretion, visibly demonstrated by the nasal mucous membrane after ‘oxyl-iodide’ has been taken for some time. The general action on mucous membranes favors elimination of toxins and waste products.”

It is probable that “oxyl-iodide” acts as a uric acid eliminant, though there is no reason to suppose that it is more effective than cinchophen alone. No data are given for this in the manufacturer’s literature.

USES

Successful use of “oxyl-iodide” is claimed in brachial and sciatic neuritis, lumbago, muscular rheumatism, arthritis deformans, chronic arthritis (“... in some instances were apparently cured”), subacute bronchitis, circumflex neuritis, traumatic orchitis, eczema and rheumatism. However, a careful reading of the protocols of seven cases, representing these conditions, gives an unfavorable impression as to the real contribution to the recovery by, or value received from, “oxyl-iodide.” Summarized, the opinions as quoted by the manufacturers in support of their claims for “oxyl-iodide” are briefly as follows:

Case 1. “Of course, the case is not complete yet, but I am looking for continued betterment.”

Case 2. “For two weeks past her improvement has been marvelous.”

Case 3. “The joints are still enlarged and we do not hope to clear them entirely....”

Case 4. “Undoubtedly, removal of the kidney had much to do with improvement.”

Case 5. “I think I have gotten very good results.”

Case 6. “Some apparent benefit.”

Case 7. “She is practically free from pain, and the muscle and joint stiffness is now slight.”

These inconclusive opinions certainly do not agree with the favorable impression which other portions of the manufacturer’s literature create. If the factor of natural recovery in the conditions represented by these seven cases is given due weight, little, if anything, is left to the credit of “oxyl-iodide.” Such clinical evidence as is supplied by the manufacturer indicates that the therapeutic efficiency of “oxyl-iodide” is doubtful, and not an improvement over either cinchophen or iodid.

IODISM

Iodism cannot be avoided by the use of “oxyl-iodide,” for the manufacturer’s literature states that “the dosage of ‘oxyl-iodide’ may be pushed to iodism as manifested by skin symptoms.... To avoid iodism there should be an occasional interruption of treatment.” “Oxyl-iodide,” therefore, has no advantage over ordinary sodium iodid to avoid iodism. Usually, the conditions which require cinchophen do not require the simultaneous administration of iodids, and vice versa. If administration of iodid and cinchophen together should be indicated or desirable, these can be given separately with the added advantage that the iodid can be easily reduced or withdrawn in case iodism supervenes, and the cinchophen could be continued if necessary. Since conditions do not arise frequently enough to warrant the use of iodid and cinchophen together, the existence of such a product as “oxyl-iodide” is unwarranted.

Finally, the manufacturer himself recognizes that phenylcinchoninic acid (cinchophen) can take the place of “oxyl-iodide.” Under “dosage,” the circular states: “A few patients may be idiosyncratic to the iodides and find they cannot take ‘oxyl-iodide.’ For the latter chloroxyl, the hydrochloride of phenylcinchoninic acid, is recommended.” The action of the hydrochlorid of phenylcinchoninic acid does not differ, of course, from that of cinchophen. The difficulties of assigning a clear-cut, definite, therapeutic rôle to “oxyl-iodide” in order to justify its existence, alongside well-known and tried remedies are self-evident.